TW434206B - Methods for the preparation of pyridine derivatives for preparing an antisecretory compound, omeprazole - Google Patents

Abstract

This invention describes methods for the preparation of pyridine derivatives having the formula, wherein R1 is C1-C4-alkyl, halomethyl, aminomethyl, hydroxymethyl, nitrile or carbonylamino; R2 is C1-C4-alkyl; R3 is hydrogen, halogen or OR31, wherein R31 is C1-C4-alkyl; R4 is C1-C4-alkyl; and R5 is hydrogen, halogen, hydroxy or OP(O)(OR51)2, wherein R51 is methyl or ethyl. The derivatives are for preparing an antisecretory compound, omeprazole.

Description

434206 Duty Printing Cooperative Work of Central Standards Bureau, Ministry of Economic Affairs

Μ B7 V. Description of the Invention (1) Field of the Invention The present invention relates to a novel method for preparing a pyridine derivative of formula I

Among them, i alkyl, from methyl, aminomethyl, hydroxymethyl, nitrile or carbonylamino; " R2 is C, -C4-alkyl; R3 is hydrogen, halogen or OR31, where R31 is C, -C4 -alkyl; R4 is -C4-gauge; and R5 is hydrogen'halogen, hydroxyl and OH (OH) (〇R51) 2 'wherein R "is methyl or ethyl. 3' It is related to the anti-gastric ulcer · medicine omeprazole, the starting material of the pyridine ring part and / or derivatives of synthetic intermediates, such as 2,3,5-trimethylpyridine, 2,3,5 -Trimethyl-4-methoxypyridine and 3,5 · monomethyl-4-methoxyρ ratio -2-a novel preparation method of nitrile. -S Background of the invention Omeprazole r OMe (where Me is methyl) 45H99.DOC — 4 This paper applies the national standard (CNS) A4 specification (2 丨 0X297 mm) III i HI ^ Order I '" I (Please First read the notes on the back and fill in this page again) 434206 A7 B7 V. Description of the invention (2 is-a known gastric acid inhibitor. Its pharmacological mechanism is as a proton back pump (Η + + Κ +)-ΑΤΡ; ^ Bite preparation. In Linqing η Bentian card by θ, γ The upper system is used to treat gastrointestinal infectious diseases, such as θ ulcers and duodenal membranes, 'Shenxiong *, Xiangcai'an. The synthesis of omimidazole is composed of 2-aminomethyl · 3,5 · dimethyl -4-methylg &&;; mercaptobenzimidazole is obtained through two steps of coupling and oxidation: OMe 乂 广 XXVs'm

Η Μ = Na, Κmethinopyridine and 5-methoxy

OMe --------- k-- (Please read the precautions on the back and fill in this page again.) The policy of the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (where Me is based) I European patent EPOOOSHMHTW has been It is revealed that 2,3,5-trimethylpyridine and its derivatives are important starting intermediates for the synthesis of omimidazole, 2-aminomethyl_3,5_dimethyl_4-methylpyridine, And revealed its synthesis method. A method for preparing 2,3,5-dimethyl p-biting has been disclosed in the patent literature. For example, Japanese Patent Application No. JP 59-146620 discloses that Raney Nickel mixed metal catalyst catalyzes the reaction of 3,5-dimethylpyridine and methanol to generate 2,3,5 ▲ Trimethyl eutectic. This process requires the use of expensive and expensive high-pressure equipment, which is dangerous in operation, and has a regulated secondary product formation, which makes the product fractionation process quite complicated. U.S. Patent No. 5,061,805 discloses the use of excess sulfur powder to cleave 2-alkyl-3,5-dimethyl, the second-chain long-chain anti-group at the second position into methyl groups to generate 2,3,5- Trimethyl tt than bite. This method requires the use of a large amount of flammable sulfur powder, which is not only risky, but also by-products can easily cause environmental pollution, and the source of the starting material is not easy to obtain. The paper size of the US patent applies to the Chinese national standard (CNS) A4 (210X297 mm)-ordered by the Central Bureau of Standards of the Ministry of Economic Affairs and printed by the Consumer Cooperatives A7 B7 V. Description of the invention (3) 4'785, 113 The tf is based on 3-amino-2-methyl. Ethyl butenoate and ethyl monomethylmalonate as starting materials, and an unstable intermediate is obtained through a condensation reaction, and then 2 is obtained through empirical decomposition. 4 -dihydroxy_ 3,5,6 • trimethylpyridine, followed by treatment with difficult gas to obtain 2,4 -digas · 3,5,6 -trimethylpyridine, and finally catalytic hydrogenolysis reaction 2,3,5-trimethylpyridine was obtained, in which the condensation reaction was carried out in the presence of highly dangerous sodium sand, and the gasification reaction required the use of 4 equivalents of cool gas to generate a large amount of wastewater after neutralization ^ However, the above-mentioned method of manufacturing plutonium is still not very satisfactory. For example, the preparation of 3-amino- · 2-methyl-butenoic acid ethyl ester must be performed in an autoclave, so it must have more expensive equipment and It is dangerous; the yield of 2,4-dienyl_3 5,6-trifluorenylpyridine is not good (40-50%), which shows that the condensation reaction is still accompanied by its In order to overcome the above difficulties, we have researched and invented a novel method for preparing 2,3,5-trimethyl u ratio bite. About 2-¾methyl-3,5-di * ψ group The synthesis of 4-methoxymethoxy bitumen has also been revealed and shown in previous techniques. For example, the following two representative patents disclose the ratio of 2-Methyl-3,5-dimethyl-4-methoxy p The preparation method is as follows, in which the European patent EP 0 005 129 (1979) is based on 2,3,5 · trifylpyridine as the starting material, and the material is obtained through oxidation, nitration and methylation (step ⑴) to obtain 2,3, 5 'trimethyl-4 -methoxypyroxide' and then undergo a halogenation reaction (step ⑷), hydrolysis reaction (step ⑽) to obtain 2-hydroxymethyl-3,5-dimethyl-4 -methyl Oxypyridine, while German patent DE 3840372 (1988) uses 3,5-dimethyl-methyl bite as the starting material, 'oxidation, nitration and cyanation (step ⑸_ (70 to get 2 _ cyano-3,5 -Dimethyl-4-nitropyridine, and then through a methylation reaction and a hydrogenation reaction (steps ⑼-⑼) to obtain 2-aminomethyl-3,5 · dimethyl-4 _methoxy This paper is applicable to China National standard( CNS) A4 is now (210X297 mm) —--------'— (Please read the precautions on the back before filling in this page) Order. ^, I · 434206 ^, A7 B7 V. Description of the invention (4 groups are pyridine, and then undergo diazotization hydrolysis reaction (step ⑼) to produce 2 u supermethyl • 3,5-dimethyl-4 -methoxypyridine. 2_ Methyl-3,5-dimethyl-4-methoxypyridine can be further vaporized in accordance with the method known per se to obtain the starting material for the synthesis of omidimazole, 2-aminomethyl-3,5-di Methyl-4.methoxypyridine (step (12)). The reaction formula is as follows:

Please note back och3

2_Methyl-3,5-diasyloxypyridine item Λ Fill in this page (1) H202 / H0Ac (4) Ac20 • (7) (i) (CH3) 2S〇4 (10) NaOH / CH3OH, (2) HN〇3 (5) H202 / H0Ac (ii) KCN H20 (when RCH2OAc (3) NaOH / CH3OH (6) HN03 (8) CH3ONa / CH3OH), H20 (9) H2j Ra-Ni (11) (i) NaN02 / H0Ac, 〆H20, (ii) NaOH / H20 ', (when printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ^ (12) (i) SOCl2⑼Zhonghebu (where Ac is gH3CO) »The methods disclosed in European Patent EP 0 005 129 (1979) or German Patent DE 3840372 (1988) are not very satisfactory because they all use pyridine derivatives as starting materials and / or intermediates, among which The nitrification and oxidation reactions involved are highly corrosive and the nitropyridine and its oxides are potentially carcinogenic. This paper size is applicable to Chinese national standards (CNS > Λ4 specification (210X297)) A7 B7 V. Description of the invention ( 5 In order to avoid the above shortcomings, we have studied and invented different ways to prepare 2-methyl-3,5-monomethyl-4-fluorenyl p ratio. The method of the present invention is characterized by linear Starting material T synthesized with an appropriately substituted derivative group bite, rather than a cyclic or pyridine derivative as a starting material. The present invention is described in detail object of the invention to provide a process for preparing a compound of the formula la and their derivatives 'method, -'

Printed by the Offshore Consumers Cooperative of the China Standards Bureau of the Ministry of Economic Affairs Λ ο

45399. DOC The steps are as follows: ⑴ Dehydration reaction of the compound of formula j_ with the starting material of formula BCH2 NH2 (where B is a phenyl substituted phenyl group) to form a protected amine of formula 1 R2 \ ^ C02C2H5 R2 \ ^ C〇2C2H5 Ν ι ch2b ⑵ The formula VII protected '% is an amine ester and a reagent capable of supplying an alkyl cation to undergo an alkylation reaction to form an alkylated alkyl amine ester derivative. 〇 『r1XnA ^ R4 2;

I ch2b (3) The formula 2_burned fluorenated enamine ester derivative is treated with strong alkali and heated to be divided into -8-the paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 434206 ^ A7 B7 V. Description of the invention (6 sub-cyclization to form ketone derivative OH, R4

4 Alkylation of the derivative of formula 1 to obtain a compound of better solubility. The compound of formula I is subjected to a hydrogenolysis reaction to obtain a compound of formula I OR31 .R4

ch2b OR- 31

--------- k-- (Please read the precautions on the back to fill in this page first.) Employees 'Cooperative Cooperatives' Seal, Central Procurement Bureau, Ministry of Economic Affairs, 33---6 (where R31 is q-C4 alkyl) ; 反应 reacting a compound of formula with a phosphonium halide to form a compound of the formula X ~ .R + Eight X: where «= * ·» (where X is a halogen); Removal from the prime atom gives the product of formula U (where R1 is Ci_C4 alkyl and hydrazone and min 5 are hydrogen)

In the above step ⑴, the preferred BO ^ NK is: amine, and the dehydration is 9-This paper size is applicable to Chinese national standards (CNS > Μ specifications (210X297 mm>

1T rr A7 B7 V. Description of the invention (7) It should be carried out in benzene and with P_TSA as catalyst. In step (2), the preferred reagent that can supply poland cations is propionium cations, such as propane gas or liver propionate. Step 3 (preferably in the presence of a deacidifying agent and optionally in toluene or methyl tertiary butyl) It is carried out in the presence of an ether, and preferred examples of the deacidifying agent are pyridine, propylene oxide or tertiary amine. The alkylation reaction is preferably performed at 40 ° C., most preferably at 50 ° C. The preferred examples of the strong base used in the intramolecular cyclization reaction in step (3) are sodium hydride and t-butanol. Or sodium amidate, and the intramolecular cyclization is preferably carried out in a bulk agent; the hydration reaction of step 较佳 is preferably carried out in the presence of -xin (: 03 / propyl net, and more The calcination reaction with a dialkyl sulfuric acid is preferred. Step ⑸ is preferably carried out at 110-130 ° C, and is most preferably performed at 120 ° C. Among them, the preferred phosphorus compounds are phosphorus and chlorine and scale. And the hydrogenolysis reaction of step ⑹ is preferably carried out in the presence of a deacidifying agent, the preferred examples of the deacidifying agent are ammonia and ethanol, and the gasolysis reaction is preferably carried out at 1¾ 2 / Pd-C. According to the present invention, Preferred compounds of formula la in which ri, R2 and R4 are methyl groups and R3 and R5 are hydrogen (ie, 2,3,5-trimethylpyridine). Compared with known techniques, the method of the present invention has many advantages, For example: (1) Protected formula enamines can be made under normal pressure, and do not need to be carried out in the middle of the whole process; and the policy of employee consumer cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please first (Please read the notes on the back of the page and fill in this page again.) ≫ (U) The intermediate formula ratio / copper compound has development potential, for example, it can further prepare formula Ίΐ) and ic. Another object of the present invention is to provide a preparation formula Method for lb compound and its derivatives 45099. DOC ^ This paper is in accordance with the Chinese National Standard (CNS) 21GX 297 mm) 434206 A7 B7 V. Description of the invention (8

Where R1, R2 and R4 are Q-C4-alkyl; R3 is OR31, where RM is QC4-alkyl; and R5 is hydrogen, hydroxyl, and OP (〇K 〇R5i) 2, where R "is methyl Or ethyl, which includes the following steps: (1) the hydrogenated ketone adduct of formula b is carried out with Hal P (Ο) (〇R5i) 2 (where Hal is halogen and RM is methyl or ethyl) After the phosphating reaction, a hydroxypyridine derivative of the formula I and a pyridine derivative of the formula OR31 r ^ 〇31 OR were obtained, respectively. "

N ^^ OH

八 ΟΡίόχΟί ^, (Please read the precautions on the back before filling in this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 8 9 ⑵ 式 i_ Compounds can be further reduced according to the situation to obtain the formula than the bite street organism (Form lb, Where R1, R2, and R4 are Ci-C4 -alkyl; RJ is OR31, where Rsi is QC »-alkyl: and R5 is hydrogen)-OR31!, R4 10 0 Compounds of formula 获得 obtained by this method may be further processed as appropriate. To give a pyridine oxide of formula U.

The paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210 · × 297 mm) Q) 4 4

CL A7 B7 Consumption cooperation of employees of the Central Bureau of Standards of the Ministry of Economic Affairs Du Yinzhuang 5. Description of the invention (9)

R4 The steps of this method are preferably carried out in tetrahydro 11-furan, and the hydrogenation reaction is preferably carried out with NaH for 3 steps. The most preferred method is to select lithium, sodium, ping or drinking metals in liquid ammonia. The reduction reaction is carried out in the medium, and the preferred one is Jing. In this step, "proton supply reagents such as tertiary butanol can be added in sunny conditions. This further oxidation reaction is preferably performed with hydrogen peroxide in an acetic acid aqueous solution. The obtained formula JJj, pyridyl oxide can be converted into fluorenylmethyl substituted pyroxypyridine of the following formula by a method known per se. OR31

(Where X is halogen, R2, R31 and R4 are as defined above). A preferred embodiment of this method is the ratio of 2,3,5-trimethyl-.4-methoxyl u (ie formula lb, where Ri, R2 and R4 are >groups; R3 is methoxy and R5 Those who are hydrogen) of · Preparation. Λ 'By this method, the 2,3,5-trimethyl-4-methoxypyridine obtained may be further oxidized according to circumstances to obtain 2,3,5-trimethyl-4-methoxypyridine oxide. The 2,3,5-trimethyl-4-methoxypyridine oxide obtained can then be converted into the starting material 2-aminomethyl'3,5-dimethyl- 4-methoxy ratio lake, the detailed operation process of this conversion has been disclosed in the European patent EP 0 45 3 9 9. DOC-* 12 — This paper size applies to China National Standards (CNs) A4 specification (21 〇X 297mm) --------- install ---'-- l · order (please read the precautions on the back first_ «fill out this page) A7 B7 R3 -R4

434206 V. Description of the invention (10 005 129 (1979). Another object of the present invention is to provide a method for preparing a compound of formula Ic and its derivatives, a method for producing a compound j 1 to a human.

Ic wherein R1, R2, and R4 are C! -C4-alkyl; r3 is or31 or R-wherein R31 is a C, -C4-¾ group; and R5 is a self-prime. It includes the following steps: reacting a compound of formula Tpyridone with an autochemical reagent to obtain a mixture of the monodentate product of Formula 1 and the product of 2-bichemical product I. ^ (Please read the precautions on the back before | fill in this page )

OR31 X

12 7 (where X is defined by prime, R1, R2, R3i, and R4 are as previously defined) β Order Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs The reaction is preferably 60-8 (5 ° C, and the best halogenating reagent is a gasification reagent, such as p0ci3, SOCl2 or R'R ", P (〇) Cl (where R1 and R " respectively It is an alkyl group or a phenyl group). The proportion of the mixture produced varies according to the reaction conditions. The compound of formula 1 can be further hydrogenolyzed to obtain a compound of formula

.DOC -13 The size of this paper is applicable to China National Standard (CNS) A4 (210X297 mm) 434206 A7 B7 V. Description of the invention (11 OR31

OR31

R4 12 This hydrogenolysis reaction is preferably carried out with Η 2 / P d · C in ethanol and liquid ammonia. The reaction product of the preferred embodiment of this method is 2 -Ga-3 5 6-= Tian Ji-′ 7 ~ Ya Bao '4 -methoxypyridine. The 2,3,5_trimethyl_4_methoxypyridine obtained from the hydrogenation of this product can be made into the enantiomeric substance 2-omethyl-3,5- Dimethyl-4-methoxypyridine. Another object of the present invention is a method for preparing compounds of formula Id and derivatives thereof R3

(Please read the notes on the back before filling out this page) • Discard. B Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, R4 Id, where R1 is from methyl, aminemethyl, hydroxymethyl, nitrile Or carbonylamino; R2 and R4 are C1-C4-alkyl; R3 is OR3> (where R3 丨 is Ci_C4 alkyl); and R5 is hydrogen. .. It uses ketone derivatives as starting materials and uses its derived piperidine derivatives as w as key intermediates and raw materials. # The derived pyrone derivatives are converted to pyridine of formula Id by appropriate functional group conversion. derivative. The detailed steps are as follows: (1) The starting material of the following formula 1 ^ _ (which can be referred to described in " Organic Synthesis (Organic Syntheses) 'Volume 70, 231 (1991) " Obtained) and alkane compound R6X (where R6 is C, -C4 -alkyl and X is halogen). Oxyalkylation under basic conditions to obtain the compound of formula 1; 14--a Γ This paper size is applicable to Chinese national standards (CNS) ί \ 4 specifications (2lOX297 male t) 434206 A7 B7 V. Description of the invention (12)

OH R2

14 13 ⑵ The compound of the formula and diethyloxalic acid g§ are tested under the same conditions. At the same time, the ring is also produced to produce formula, acetic acid and formula citrate.

And H02c, 〇 r〇2c

16 (Please read the precautions on the back and fill in this page again.) 15 ⑶ The formula is omitted. Brew in an autoclave and heated for amination and simultaneous amination to obtain the formula 12_pyridone amide derivative R2iV H2N (0 C) R4 17 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs OR 31

R4 18 Η ⑷ alkylates the formula IZj ^ ketoamine amine derivative 11 under alkaline to form the alkylated product of formula 1B

Remuneration 0) C eight N (R31 is C!-C4-environment-based) ⑸ The slope-based product is treated with a dehydrating agent to obtain a high yield formula! £ _

45899.DOC This paper size applies to Chinese national standards (CNS > A4 size (210X 297 mm) 434206 A7 B7 V. Description of invention (u Nitrile derivative OR31

R4 19; The product of ⑹Formula 1_2_ can be obtained through the catalytic reduction of the catalyst to obtain the compound of formula & 曱 amination 谙 first heard read back term OR31

R4 H2Ns Page 20 Benzene methylamine compound can be obtained by diazotization and detection hydrolysis to obtain compound of formula 21_. OR31

R4 'N Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economy OR31

HO. * 21 (8) The compound of formula 21 may be halogenated to obtain the compound of formula 22, R4 22 — (wherein X is self-prime, and R2, R31 and R4 are as defined above). Among them, hydrogenation, diazotization, hydrolysis and southernization are known techniques (see DE 3840372, this paper size applies Chinese National Standard (CNS) A4) (21〇: < 297 mm) 434206 A7 B7 V. Description of the invention (l4 ) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (1988)) 〇The arkanide in step 较佳 is preferably bromoethane, and the oxyalkylation is preferably based on Kζ (: 〇3 as alkaline Compounds and in the presence of two ketones. Preferred examples of the basic compounds used in the synthesis of pipe beer in step ⑵ are sodium ethoxide, potassium t-butoxide or sodium amidate, and the reaction is preferably performed in sodium ethoxide / ethanol. Step (3) is preferably carried out with ammonia in ethanol. The calcination reaction in step (2) is preferably carried out with dioxosulfuric acid and K2CO3 as the basic compound in the presence of propylene network. "Step (2)" Examples of the dehydrating agent include a mixed reagent of trifluoroacetic anhydride and -exopyridine, phosphorus pentoxide, phosphine gas, phosphorus pentafluoride, dimethylformamide / acid, dimethylformamide dimethyl Acetal and sulfite gas punches, preferably a mixed reagent of trifluoroacetic anhydride and pyridine, which The preferred reaction temperature is from 0C to room temperature 'and the reaction can be carried out in methane. The preferred reaction product of this method is 3,5-dimethyl-4-methoxypyridine-2-nitrile (ie formula M (Where R1 is CN, R2, and R4 are methyl, R3 is methoxy, and penta R5 is ammonia). The 3,5-dimethyl-4 · methoxypyridine-2 -nitrile may be as described above. An important synthesis of 2-o-methyl-3,5-di-1 i-4 methoxypyridine through hydrogenation, diazotization, and hydrolysis, which can be reused by the previously known methods to obtain omimidazole through chlorination The starting material is 3-airino-3,5-dimethyl-4-methoxypyridine. Example, Ethyl-3 -amidoethyl butenoate ethyl monoethylacetate ethyl acetate (28.8 G, 0.2 mol), amido (21.4 g, 002 mol) and p-toluenesulfonic acid monohydrate (0.4 g, 0.02 equivalents) were sequentially added to the benzene solvent (300 ml), then heated under reflux and dean -The size of the paper received by the Stark device is in accordance with the Chinese National Standard (CNS) M specifications (210X297 mm). Please read the notes on the back and fill in this page. ^ 34206 A7 B7 Du Yinze V. Description of the invention (is) The azeotropically distilled water is collected. After about 3.5 hours, the water no longer precipitates. The resulting solution is cooled and washed twice with water, and the organic layer is dried and concentrated over anhydrous sodium sulfate. The residue was subjected to vacuum distillation to obtain the target compound (41.8 g, 99.7%). LH NMR (CDC13, 200 MHz) 9.67 (brS, 1H), 7.20-7.40 (5H), 4.45 (2H, J = 6.2Hz, 2H), 4.17 (g, J = 7.2Hz, 2H), 1.95 (S, 3H), 1.83 (S, 3H), 1.31 (t, J = 7.2Hz, 3H) «2 -methyl-3 -propanamidinate Ethyl-butenoate Ethyl 2-methyl, 3-ethyl: amino-butenoate (44.7 g, 0.204 mol) and pyridine (20,2 g, 0.255, mol) were added to toluene ( 70 ml), followed by instillation-a solution containing propanium (18.9 g, 0-204 mol) in 30 ml of toluene. It was then heated under reflux overnight, and the resulting solution was filtered and concentrated. The residue was diluted with ethyl acetate, then washed with water, dried and concentrated to obtain the target compound (56 6 g, 96%) = NMR (CDC13, 200 MHz) 7.10-7.25 (m, 5H), 4.97 (d, J = 14.30 Hz, 1H), 4.24 (d, J = 14.30 Hz, 1H), 2.40 (g, J = 7.0 Hz, 1H), 2.10 (g, J = 7.0 Hz, 1H), 1.85 (S, 3H), 1.70 ( S, 3H), 1.20 (t, J = 7.0 Hz, 1.5H), 1.14 (t, J = 7.0 H & 1.5H). In addition, 2-methyl-3-amidoamino-butenoic acid ethyl ester / propane gas and excess (10-20 volume ratio) propylene oxide were heated to 50 in a methyl tert-butyl ether solvent. (; And maintain the number is small. Then, after the ^ agricultural shrinkage and air heating, it can also be generated after the target compound. N-fluorenyl-4-hydroxy-3 ~ Γ5,6-trimethyl-2-pyridone will 2-Methyl 3-propionated amidino-butenoic acid ethyl ester (53.8 g, 0.196 mol) and 60% sodium hydride (22 g, 2.8 equivalents) were sequentially added to ice-cold dry benzene solvent (240 ml) +, Then heated at reflux for 8 hours. The resulting solution was made slightly acidic with 6N HC1 under ice bath, and the precipitated white solid was filtered and dried to obtain the target compound (41 g, 86%). The melting point was 263 ° C. NMR (6d-DMSO , 200 MHz) This paper size applies to Chinese national standards (CNS > A4 specifications (2〗 〇 > < 297 mm) --------- installation-(Please read the precautions on the back first (Fill in this page) Order the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 434206 A7 B7 V. Invention Description (16) 9.24 (S, 1H), 7.00-7.30 (m, 5H), 5.30 (sb, 2H), 2.18 ( S, 3H), 1.94 (S, 6H); Ms (m / e, rel intensity) 243.2 (M +, 100), 228.2 (5); Elemental analysis (Ci5hi7N〇2): Calculate 値 C, 74 · 07; H, 7.00; N, 5.76; Measured 値 C, 74. 01; H, 7.01; N, 5.80 »N-benzyl · 4-methylamidino-3,5,6-trimethyl-2-pyridinium will be N-benzyl-4-meryl-3,5, 6-Trimethyl-2-E- (15 g, 0.062 mol), anhydrous potassium carbonate (17 g, 0.12 mol) and dimethyl sulfate (9.3 g, 0.074 mol) were added in order acetone (300 ml) Then, the solution was heated under reflux overnight. After cooling, the resulting solution was filtered and concentrated. The residue was diluted with ethyl acetate, washed with water, dried, and concentrated to obtain the target compound (14.66 g, 92%), which was a white powder. 169 ° C. Tun NMR (CDC13, 200 MHz) 7.10 7.35 (m, 5Η), 5.42 (sb, 2H), 3.75 (S, 3H), 2.23 (S, 3H), 2.16 (S, 3H), 2.04 (S, 3H); Ms (m / e, rel intensity) 257.2 (M +, 100). 4-Methoxy-3,5,6 · trimethyl-2-pyridone was added to the hydrogenation bottle in order. --Amidino-4 -methoxy-3,5,6-trimethyl-, 2-pyridine (23 g, 0.089 mol), glacial acetic acid (150 ml) and 10% Pd-C (2 G) 'Then shake at argon at 60 Psi for 2 hours. The resulting solution was filtered through Celite and subjected to reduced pressure. The residue was adjusted to slightly alkaline with f0% potassium carbonate in water. The precipitated solid was filtered, washed with water, and dried to obtain the target compound (M.6 g,), which is A white powder, melting point 194X: »屮 NMR (CDC13, 200 MHz) 13.04 (brS, 1H), 3.73 (S, 3H), 2.31 (S, 3H), 2.08 (S, 3H), 1.98 (S, 3H) ; Ms (m / e, rel intensity) 167.1 (M +, 100), 152.1 (2); Elemental analysis ((: 9 leaves to 0 2): Calculate 値 c, 64.67; H, 7, 78; N, 8.38; Found 値 C, 64.94; H, 7.87; N, 8.45 = 2,4-digas-3,5,6-trimethylpyridine and 2,4-dibromo-3,5,6-trimethyl 45 & 99 * DOC 19-This paper size applies to China National Standard (CNS) A4 (210X297 mm) --------- k-- (Please read the precautions on the back before filling in this page) Order 434206 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the Invention (l7) Ye Diandian will be 4-methoxy-3, 5,6-trimethyl-2-pyrone (8 grams, 0.048 moles) and scale fermentation gas (7.34 g, 0.048 moles) were heated at Π0 C for 30 minutes; Erqi Jiayuan was diluted with crushed ice. The organic layer was separated and adjusted to 100% with carbonic acid. Then it was washed with water, dried, and concentrated to obtain 2,4_ 二 气 _ 3,5,6. Methylpyridine (8.2 g, 90%), which is a white powder crystal, melting point 66-68. (: ： NMR (CDC13, 200 MHz) 2.42 (S, 3H), 2.36 (S, 3H), 2.24 (S ， 3H) ^ If Phosphonium bromide (13.8 g, 0.048 moles) is used instead of Phosphonium gas to obtain the same operation-2,4-dibromo-3,5,6-trimethyl u ratio (12.7 g, 95 %), Falling point 50- 52 eC. Ή NMR (CDC13, 200 MHz) 2.54 (S, 6H), 2.35 (S, 3H). 2, 3, 5-trimethylpyridine 2,4-digas- 3,5,6-trimethylpyridine (9.5 g, 0.05 mole) or 2,4-dibromo-3,5,6-trimethylether (14 g, 0.05 mole) is dissolved in i -3wt% Zhao catalyst in a mixture of ethanol (100 ml) and ammonia (10 ml), and then shake under the hydrogen pressure of 40 Psi gauge until the end of the reaction (about 5 hours), filter to remove the catalyst The filtrate was concentrated to obtain a mixture of vaporized ammonium (or ammonium bromide) and 2,3,5-trimethylpyridine. Chlorofane was bubble-washed and filtered, and the filtrate was washed with water, dried, and concentrated to obtain 2,3,5-trimethylpyridine (5.8> g, 95%). It is 1 oily liquid tun (CDC13, 200 MHz) 8.14 (S, 1H), 7.22 (S, 1H), 2.44 (S, k), 2.25 (S, 3H), 2.23 (S, 3H). The results obtained are the same as those of the standard. 2-Diethylphosphoryl-4 -methoxy-3,5,6-trimethylpyridine Under nitrogen, add 60% sodium hydride (0.263 g, 6.59 mmol) to a 50 ml bottle with 5 The milliliter of tetrahydrobitan is used to wash off the oil and extract it with a needle, and then inject 45B99 .DOC — 20-This paper size applies to China National Standard (CNS) A4 (210X297 mm) III 111 Order r (Please read the note on the back first) Matters- * soil write this page) 434206 A7 B7_ V. Description of the invention (is) Tetrahydroanal (30 ml) and 4-methoxy-3,5,6-triamyl _ 2 _ Ana (lo g , 5.99 millimolar) 'After incubation at room temperature for about 30 minutes, inject the acetic acid reagent diethyliphosphine thoron gas (diethyiphosPhoryl chloride) and incubate overnight ° and then depressurize and extract the tetrahydrocran' residue The solution was diluted with 100 ml of sodium oxide aqueous solution, and then extracted with Sanqijiakeng. The organic layer was washed with water, dried, and concentrated to obtain the target compound (1.82 g, 100%). 'It is a viscous oil.' Proceed to the next step. lH NMR (CDC13, 200 MHZ) 4.41 (g, J = 7.2 1¾ 4H), 3.74 (S, 3H), 2.38 (S, 3H), 2.15 (S, 3H), 1.43 J = 7.2 Hz , 6H). 2.3.5-Trimethyl-4-methoxypyridine Method A: To ensure that the liquid ammonia is anhydrous, first condense the liquid ammonia in a 250 ml three-necked flask, and then add about 0.1 g of lithium metal. Blue, then remove the cold bath to volatilize the liquid ammonia and condense again into another 1⑻ml three-necked flask to collect about 50 ml of liquid ammonia. Next, a solution containing 2-diethylphosphono-4-methoxy-3,5,6-trimethylpyridine (5.54 g, 18.3 mmol) in 14 ml of tetrahydrofuran was added dropwise, and then weighed in advance For good metallic lithium (.381 g, M.85 mmol), the color of the solution changed from colorless to light or even orange-red. After 4 minutes and 15 minutes, add hydrazine (2.96 g, 55.33 mol) and let the liquid ammonia evaporate. The residue was added with 100 ml of water, and the extract was dried and concentrated to obtain an oily substance, which was separated by column chromatography. The extraction solvent was ethyl acetate and n-hexane ( 1: 5), 2,3,5-trimethylpyridine (0.22 g, 10%) and the target compound (0.97 g, 35%) were obtained in sequence, which is a colorless oily β βιι ruler (CDC13 , 200 MHz) 8,15 (S, 1H), 3.75 (S, 3H), 2.46 (S, 3H), 2.22 (S, 3H), 2.19 (S, 3H) »and 4 -methoxy-3, 5,6-trimethyl-2-pyridone (0.46 g, 15%). .DOC-21 — Applicable to Chinese National Standards (CNS > A4 now (210X 297mm) ~~ (Please read the precautions on the back before filling in this page). Order the staff of the Central Bureau of Standards of the Ministry of Economy Cooperative, printed by 43420t A7 B7 V. Description of the invention (19 Method B: Please read the notes on the back L # The 2-diethylphosphoryl group_4_methoxy-3,5,6 -trimethyl Pyridyl (24 g, 0.144 mol) and phosphonium gas (22.02 g, 0.144 mol) (or in the presence of 10-20 volume ratio of dry 1,2 digas ethane) at 60-7. (: Heating for 5 hours; after cooling, the resulting solution is diluted with three gas methane and crushed ice, the organic layer is separated to make it slightly alkaline with 100/0 potassium carbonate, and then washed with water, dried and concentrated to obtain 2 , 4 Digas · 3,5,6-trimethylpyridine and 2-Ga-3,5,6-trimethyl-4-methoxypyridine mixture. This mixture is based on 2,4-Digas-3, The hydrogenolysis of 5,6-trimethylpyridine was used to obtain a mixture of the target compound and 2,3,5-trimethylpyridine ', and then 2,3,5-trimethylpyridine (9.53 G, 54.7%) with standard Compound (5.94 g, 27.3%) of 2,3,5 - trimethyl - 4 - methoxy Bauer Oh oxide

Consumption cooperation among employees of the Central Bureau of Standards, Ministry of Economic Affairs. Du Yin 1L 2,3,5-trimethyl-4-methoxypyridine (3.2 g, 20 mmol) was dissolved in 10 ml of glacial acetic acid, and then dropped 5: 0 ml of 30% hydrogen peroxide aqueous solution, first stirred at 30 ° C for 1 hour, then rose to 7 (TC for 5 hours, and finally rose to 90 1) and then add a small amount of powder to complete the process. Hydrogen oxide. After returning to room temperature, the solvent was concentrated and the solvent was removed. The residual solution was concentrated by adding benzophenone # to remove the residual compound (2.84 g, δ5%). Melting point 35 ° C, β NMR (CD03, 200 MHz) 8.2a (S, 1H), 1.80 (S, 3H), 2'50 (S, 3H), 2.25 (S, 6H). The results obtained are the same as those of the standard. 2-methyl-1-戍Ene-1 -ethoxy-3 -one The starting material 2-methyl-1-penten-1-ol-3-one (76 g, 0.67 moles) was dissolved in acetone (1500 ml), then Ethyl bromide (209 g, 1.92 moles) and anhydrous potassium carbonate (115 g, 0'83 moles) were added and the mixture was heated under reflux for 34 hours.

, DOC This paper uses Chinese National Standards (CNS) A4 specifications {21 ο X 297 mm) 434206 A7 B7 Reprinted by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (20) The filtrate was concentrated and diluted with water. The diluted solution was extracted twice with ethyl acetate. The organic layer was washed with dilute potassium carbonate aqueous solution and washed with water, then dried, concentrated and distilled under reduced pressure to obtain (80.3 g, 84%). Boiling point 62 ° C (0.82 mmHg), NMR (CDC13> 200 MHz) ^ 7.33 (S, 1H), 4.08 (q, J = 7.2 Hz, 2HX 2.56 (q, J = 7.4Hz, 2H), 1.73 (S, 3H), 1.36 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 7.4Hz, 3H) »3,5-dimethyl-4- ¥ 唏 -2-carboxylic acid and 3,5-di Methyl-4-piperazine-2-ethylcarboxylic acid ester-2-Methenyl-1 -pentamidine-1 -ethoxy-3 -one (4.05 g, 0.028 mole) with diethyloxalic acid The mixed solution of the ester (4.1 g, 0.028 mol) was dropped into 50 ml of 0.626 M ethanol solution under reflux, which took about 0.5 hours. Then continued heating under reflux for 0.5 hours. The resulting red solution was concentrated and poured into crushed ice. Extracted twice with trioxane, combined The solution was washed with water again. The washing solution was combined with the aqueous layer and adjusted to acidity with 6N HC1, and then a precipitate precipitated out. The 3,5-dimethyl-4-piperazine-2-carboxylic acid (3,5-dimethyl-4-piperazine-2-carboxylic acid ( 0.94 g, 20%), which is a white powder, melting point 185 stomach 187 ° C (3: 1 ethyl acetate / benzene), Ή NMR (DMSO-d6), 8.19 (S, 1Η), 2.15 (S, 3Η) , 1.83 (S, 3H) rMs (13 ev) m / z-(%) j 168.0 (M +, 100), 124.1 (20), 95.0 (20). The organic layer was concentrated under reduced pressure, and the residue > The Λ-Kun mixture of alkane and diethyl ether was diluted and cooled to 0 4c, and then a precipitate was precipitated. R was collected by filtration and air-dried to obtain 3,5-dimethyl-4-piperazine-2-ethylcarboxylic acid ester (2.28 g , 40%), which is a white powder, melting point 81-83 ° C (1: 4 ethyl acetate / n-hexane), NMR (CDC13), 7.73 (S, 1H), 4.42 (q, J = 7.2 Hz, 2H), 2.31 (S, 3H), 1.96 (S, 3H), 1.42 (t, J = 7.2 Hz, 3H), Ms (13 ev) m / z (%): 1% · 1 (M +, 45) , 167.1 (100). 45d99.DOC-9 3-* ----------- (Please read the notes on the back before filling in this page) The size of the paper is applicable to China National Standard (CNS) A4 (210X 297) (%) 434205 A7 B7 V. Description of the invention (21) g, 5-dimethyl-4-piperazine-2-carboxylic acid is esterified to 3, 5 -dimethyl-4 Glyoxylic acid was dissolved in 3,5-dimethyl-4-piperidin-2-carboxylic acid (3 g, 17.85 mmol) in anhydrous ethanol (30 ml), and then 0.5 g of concentrated sulfuric acid was added dropwise. The mixture was heated under reflux for 5 hours and then concentrated under reduced pressure. The residual solution was diluted with three gas methane and then washed with water and 10% sodium bicarbonate aqueous solution. The organic solution was concentrated by drying to obtain 3,5-dimethyl-4 -piper ·, Allyl 2-ethylcarboxylate. 2-Carboxamidamine-3, dimethyl-4-pyridone In an autoclave, add 3,5-difluorenyl-4-piperazine-2-ethylcarboxylic acid ester (10.2 g, 52.0 mmol) ) And 180 ml of a saturated ethanolamine solution and placed on an oil bath, and then heated and stirred for 48 hours in a closed condition, wherein the temperature of the oil bath is maintained at 120 ° C. After the solution was allowed to cool, a large amount of white solids precipitated, collected by filtration and air-dried to obtain 6.2 g of the target compound, and the filtrate was reduced under reduced pressure. The residue was milled and filtered with ether, and 1.7 g of the target compound was air-dried. The combined secondary yield is 7.9 g (91%) »It is a white powder with a melting point greater than 300 ° C, NMR (6d-DMSO), 8.02 (brs, 1H), 7.85 (brs, 1H), 7.59 (S, 1H), 2.01 (S, 3H), 1.91 (S, 3H> rMs (m / e, rel intensityX 166.1 (100), 149.1 (50), 121.0 (70). Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back and fill in this page again.) 2 -Carboxamidine-5 -difyl-4 -methoxypyridine in 500 mmol of 4 acetone, and then add 2-carboxamide-3,5 -Dimethyl-4-pyrone (16.6 g, 0_1 mole), dimethyl sulfate (8 g, 0.063 mole) and anhydrous potassium carbonate (41.4 g, 0.3 mole), and then heated under reflux for 5 hours to obtain After the solution was allowed to cool, it was filtered and washed with acetone. The filtrate was concentrated under reduced pressure, the residue was diluted with water, filtered and air-dried to obtain the target compound (16.2 g, 90%). White. DOC — 2 4 * " This paper size applies to China National Standards (CNS) A4 regulations; ^ (2] 〇X 297 mm) ~ 4342 A7 B7 V. Description of invention (22 Staff Consumption of Central Standards Bureau, Ministry of Economic Affairs Cooperative printed powder, melting point 127-129 ° C, old NMR (CDC13, 200 MHz), 8.20 (s, 1H), 7.83 (sb, 1H), 5.56 (brs, 1H), 3.78 (S, 3H), 2.64 (S, 3H), 2.31 (S, 3H), Ms (m / e, rel intensity), 180.1 (M +, 100), 163, 1 (100), 135.1 (75), 105.1 (60). 2-Nitrile -3,5-Dimethyl-4 methoxypyridine in ice-cold dichloromethane (80 ml) was added with 2,3,5-trimethylpyridinyl 4-methoxypyridine (3.3 g, 18.3 mmol) in this order. Ear) with pyridine (1.6 g, 20.25 mmol), then slowly drop in i fluoroacetic anhydride (8.5 g, 38-6 mmol), and then stir at 0 ° C for 1 hour and overnight at room temperature. " The resulting solution was washed with water, 10% potassium carbonate aqueous solution and water. The organic layer was dried and concentrated to obtain the target compound (2: 7 g, 91%), melting point 56-60 ° C, NMR (CDC13, 200 MHz), 8.33 (S, 3H), 3.85 (S, 3H), 2.48 (S, 3H), 2.34 (S, 3H), Ms (m / e, re l intensity), 162_0 (100), H7.1 (80). All of the analysis data are in complete agreement with those reported by the German patent (DE 3840372 (1988)), but the synthetic strategy adopted is quite different. 2-Aminomethyl-3,5-dimethyl-4-methoxypyridine Dissolve 2-nitrile-3,5-dimethyl-4-methoxypyridine (5 g, 30.86 mmol) 160 ml of saturated methanol amine was added to 5 grams of Raney Nicket, followed by hydrogen and stirring for 3 days under a certain pressure. The resulting solution should be filtered through Celite, and the filtrate was concentrated to obtain a crude product. The crude product was subjected to vacuum distillation using a KtigeJ10hr device to obtain the target compound (3.6 g, 70%), medium NMR (CDC13, 200 MHz), 8.20 (S, 1H), 3.90 (S, 2H), 3.75 (S, 3H) , 2.24 (S, 3H), 2.21 (S, 3H), 1.94 (brS, 2H). 2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine in 43 ml of 100 /. Add 2 _ amine methyl _ 3,5-dimethyl-glacial acetic acid aqueous solution-Please read the notes on the back before writing II. 1 This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 43421 A7 B7 5 2. Description of the invention (23) 4-methoxypyridine (2.5 g, 15.06 mmol) and cooling to an ice bath, then adding sodium nitrite (3.1 g, 44.92 mmol) to water (η ml) ) And hold it at 0 ° C for 1 hour. Then, 26 ml of 4N NaOH and 50 ml of trigasmethane were added. After the organic layer was separated, the aqueous layer was extracted with 50 ml of trigasmethane. The combined organic layers were washed with water, dried and concentrated to obtain 2-hydroxy-3,5--2 Methyl-4-methoxypyridine (2.2 g, 88%). Its NMR and other analytical data were in good agreement with the standard product. According to a method known per se, this compound is reacted with thionine gas (80 (¾) and neutralized to obtain a 2-gas methyl · 3,5-dimethyl-4-fluorenyloxy p specific bite. For the convenience of explanation In the present invention, the preferred embodiments of the present invention have been described above, but it is not intended to limit the scope of the present invention. Anyone who is familiar with the art and who is capable of making artisans can modify it in any way. Attach those who want to protect the scope of the patent application. I mV flm 1 ^ 1 ^^^^ 1 Γ., (Please read the precautions on the back and fill in this page) Standards apply to China National Standard (CNS) A4 (210X297 mm)

Claims (1)

434206 Scope of patent application 1. A method for preparing compounds of formula 1 a and derivatives thereof R3. R4 1, la — C0 ′ (wherein R1, R2, and 114 are (: 1-(: 4 alkyl, and R3 and R5 are hydrogen or autogen)), this method includes: (1) a compound of the formula The starting material * · * r2, ^ co2c2h5 0 < jO and BCH2NH2 (where B is phenyl or substituted phenyl) are dehydrated to form a sulfonium ester in the protected state of the formula: ", co2c2h5 ΝΗ ch2b ⑴The obtained protected enamine ester is reacted with a reagent capable of supplying alkyl cations to perform an alkylation reaction to form an alkylated enamine ester derivative of the formula '-I ml ^ in Ι ^ ϋ · ml ml 、 1-3J (Please (Please read the notes on the back before filling out this page) CO, Et printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs CH2B cU (3) The rules obtained from ⑵ • The fluorenated enamine ester derivative is heated to undergo molecular cyclization after heating to generate the following formula _ derivative Mm) A8 B8 C8 D8 ^ 34206 6. Scope of patent application OH CH2B 规 The p obtained from ⑶ is first regularized and then hydrogenated to obtain compounds of the formula OR31 OR31 and R3 respectively (where R31 is a C, -C4 alkyl group) ^ 氢化 The hydrogenated product obtained from ⑷ Reacts with a phosphine compound to form a halogen-substituted pyridine derivative of the following formula (formula la, wherein R1, R2, and R4 are Q-Q alkyl groups and R3 and y are bovines) X n In— HI 1 ^ 1 I 1 ^ 1 I nn 11 ni ^^^ 1--SJ {Please read the precautions on the back before filling this page} 卫 4 Printed by the Consumer Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs (where X is halogen); > ⑹Shiqing Pills will be chlorinated by dentition-derived I »biten derivatives obtained by 南 to remove the sulfonium atom to obtain the following formula: Pyridine compounds (formula la, where R1, R2, and R4 are q-C4 alkyl and R3 and R4 are hydrogen) , R4 -28 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210x297 mm) 434206 6. Scope of patent application A8 B8 C8 D8 According to the scope of patent application No. 4! The method of the above item, in which the step Yinzhong of the Central Consumers' Bureau of the Ministry of Economic Affairs of the Consumer Cooperatives Co., Ltd. is ceylamine. 3. The method according to item 1 of the scope of patent application. The cation reagent is propane gas or propionic anhydride at 40-60 ° C. Also according to the method of applying for a stigma on the third item, secondary amine or propylene oxide. The method according to item 1 of the scope of patent application is sodium hydride, potassium t-butoxide or sodium amine. 6- The method according to item 1 of the scope of the patent application is carried out with dialkyl sulfuric acid at 11-13 (rc. 7 according to the method of the patent application in the park! Item ^ 笮 笮 the phosphorus in the step 醯The tritium compounds are scale fermentation gas and gamma desert, and they are carried out under the 11__. 8. 2 method of the scope of patent application, wherein step _ is performed in the presence of a deacidifying agent. 9. According to the application The method of the patent No. 8 item is ethanol. 1 The desulfurization agent is ammonia or 10. According to the method of the item No. 1 of the scope of the patent application, the compound of the formula la in China is called 2,3,5-trimethylpyridine. r Let a method for preparing a compound of formula lb and derivatives thereof, which comprises the alkane in step ⑵ and it is in the presence of a deacidifying agent where the deacidifying agent is ^ Bi Zheng, where the strong base of step ⑶ is among them Alkyl in step ------------, table ---- ^ ---- iT ------ 疒, (Please read the precautions on the back before filling this page) N, \ R5 C > 45399.DOC -29 This paper size is applicable to Chinese National Standard (CNS) A4 wash case (210X297 mm) 434206 A8 B8 C8 D8 Patent application scope (where 'R1, R2 and R4 are C | _ Q -Alkyl; R3 is OR3l, where r31 is C1-C4-alkyl; and R5 is hydrogen, hydroxyl and op (〇) (〇R ") 2, where R51 is methyl or ethyl) ⑴ will be the following formula The pyridone compound is hydrogenated and subjected to a domain quenching reaction with Hal P (0) (OR51) 2 (where Hal is _ prime and rsi is methyl or ethyl) to obtain the product via a radical derivative and Stele derivative PR31 OR31 OR31 Biological (Formula lb, wherein Ri, R2 and R4 are Q-C4 alkyl; R3 is 〇R31 ′ where R31 is C,-C4-alkyl; and R5 is hydrogen) (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs 12. According to the method of item 11 of the scope of patent application, where the steps are not selected, «C, self-included Reduction reaction of lithium, sodium, potassium or titanium metal in liquid ammonia β 13. The method according to item 11 of the patent application park, wherein step ⑵ is performed in the presence of a proton donating reagent. 14. The method according to item 13 of the scope of patent application, wherein the proton donating reagent is tertiary butanol. 15. According to the scope of patent application! !! Item 2, wherein the compound of formula (b) is 2,3,5-trimethyl-4-methoxypyridine. -30-45899.DOC This paper uses the Chinese National Standard (CNS) Rule 8 > Standard (21 × 297 mm) 434206 A8 B8 C8 D8 6. Scope of patent application 16. According to the method of item i 1 of the scope of patent application, hydrogen is oxidized to form pyridine oxide. 17. A method for preparing the compound of formula I c and its derivatives, which is further peroxidized. Ic Ύ (wherein R, R2, and R4 are Ci_Q_alkyl; r3 is 0; wherein R31 is C, -C: 4-alkyl; and r5 is halogen), which includes the following formula: The reaction of the chemical reagent 'to obtain a mixture of the product and the dual chemical product OR31 OR31' R4 R2, 丄 .r4 + Or halogen, monohalogenated X i i fl m u n »-«-I ^ n I u. I Γ (Please read the precautions on the back before filling out this page) The policy of employee consumer cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (where X is halogen). is_ The method according to item 17 of the scope of patent application, wherein the reaction is carried out at room temperature to 10 ° C., and the toothing reagent s gasification reagent therein. 19. According to the patent application No. 18 Method, where the reaction is at 6 ° C, and the gasification reagent is ρ〇α3, soQ2, rr " _ p (〇) ci (where r, and R, are alkyl or phenyl, respectively ). 2α The method according to item 1 of the scope of the patent application 'wherein, R2, and M are methyl' R3 is methoxy and R5 is gas. 21. —A method for preparing a compound of formula I d, this paper scale Applicable National Standard (CNS) M specification (210X297 male *), patent application scope 3 888 ABCD In two, R is a halomethyl'amino group, a hydroxymethyl'nitrile group or a carbonylamino group; R2 and r ^ Ci_c4 alkyl; R4OR31 (where r3i is CA · pit group); and R5 is hydrogen, The kiosk includes: ⑴ will start the following formula r * 0 R4 0H W and alkylate R6X (where 圮 is Ci_C4_ alkyl and χ is a pixel) are subjected to oxyalkylation under basic conditions to obtain compounds of the following formula; (Please read the notes on the back before filling out this page) The cooperation between shellfish and consumer goods of the Central Bureau of Standards of the Ministry of Economic Affairs. Raw piperidine η acid and piperidine ester, 〇 *, R4 ho2c And ro2c (3) The piperidine ester obtained by heating is heated in an autoclave for amination and simultaneous amination to obtain the pyridoxamine amine derivative of the following formula -32 paper Hi-Fi family standard rate 0 0 297 public 4342 06 A8 BS C8 D8 six Scope of patent application (Remuneration 0) < r, N / H 01¾ Please read ⑷The alkylation of the pyridonepyridine amine derivative obtained from ⑶ under basic conditions to form pits. Note OR31 I ⑸ treatment of the alkylated product of ⑷ with a dehydrating agent to obtain a nitrile derivative of the formula (where R2, R4 and 1 ^ 31 are (: 1-(: 4-alkyl) OR31, R4, depending on the situation, (5) The nitrile derivative is reduced by catalytic reduction to obtain the following #methylamine compound OR31 ', R4. Depending on the case, the methylamine compound of (6) is subjected to diazotization and alkaline hydrolysis to obtain the methylol pyridine compound of the following formula. Easy to use Chinese family ladder standard (CNS > A4 size (210X297 mm)) Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 434206 A8 B8 C8 D8 VI. Patent application target range OR31 Depending on the case, the product of (7) is halogenated to give the compound of the following formula Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (where X is halogen). 22. The method according to item 21 of the scope of patent application, wherein the haloalkane in step (i) is bromoethane. 23. The method according to item 21 of the scope of patent application, wherein the test compound in step (2) is sodium ethoxide, potassium t-butoxide or sodium aminate. 24th according to the scope of patent application? The method according to item 1, wherein the alkylation reaction in step (i) is carried out with dibasic sulfuric acid in the presence of k2co3 / propane. 25. The method according to item 21 of the scope of patent application, wherein the dehydrating agent in step ⑸ is selected from the mixed reagent of trifluoroacetic anhydride and pyridine, phosphorus pentoxide, riding gas, pentagasine scale, dimethyl Formamidine / acid, dimethylformamide * dimethyl acetal and Ami Gas. 1 26. The method according to item 25 of the patent application park. Mixed reagent of fluoroacetic anhydride and pyridine. 27. Method according to item 21 of the scope of patent application 3,5 · Dimethyl-4-methoxy-pyridine-2-cycline 2 Method according to item 21 of the scope of patent application wherein the dehydrating agent is three of which The compound of formula Id is in which the compound of formula Id is (please read the notes on the back before filling in this page) 34 € 34206 Μ C8 D8 VI. Application for patent scope 2-hydroxymethyl-3,5-dimethyl-4-methyl Oxypyridine. 29. The method according to item 21 of the patent application, wherein the compound of formula Id is 2-aminomethyl-3,5-dimethyl-4-methoxypyridine. Employees' Cooperatives, Central Standards Bureau, Ministry of Economic Affairs, India (Please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 (210X297 mm)