TW415948B - Process for synthesizing epoxide and halohydrin - Google Patents

Abstract

A process for synthesizing the compounds formula (I) or (II), wherein X is halo, consists of, at a minimum, electrochemical oxidation of the allyl acetonide reactant with halide salt in an aqueous system, the desired compounds being useful as intermediates for the synthesis of inhibitors of renin or HIV protease or other proteases.

Description

Revised Page of Chinese Specification for Patent Application No. 12872 (December SJJ) A7 B7 V. Description of the Invention (80Σΐ4 Allyl propyl copper 2 Allyl propyl ketal * Canonical sodium H2 0 isopropyl acetate epoxy Compound 3 a 5. 00 g (13.8 mmol) (24 mmol) 50 ml of 30 ml of medicament and solvent are mixed in a jacketed container equipped with a stirrer and an electrode made of graphite and carbon. A constant current of 0.5 A was applied and the container was kept at 20 ° C. After the reaction was completed, the product 3a was separated from carbon 3 NMR data (75.5 MHZ in CDC6) as follows: Epoxide 3: m, 140, 140, 139, 129, 128, 128, 127,] 26, 125, 1 24, 96, 78, 65, 5 1, 47, 45, 4 1, 37, 3 6, 27 and 24 Epoxide 3 a 172, 140, 140 , 139, 129, 128, 128, 127 '127, 125, 124, 97, 78, 67, 65, 44, 40, 39, 36, 27, 24 and 1 6 (Please read the notes on the back before filling out this (Page) Τ, -ιρ Example of consumer cooperation between the Central Bureau of Standards of the Ministry of Economic Affairs and Du Yinju 2

C surplus

-21-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 41594 & A7 B7 V. Description of the invention (Background of the invention This application and Merck Cases 19l82IA, 19045, 9046, 19046IA and U.S. Patent Nos. 5,1 69,952 and 5,4 13,999. The present invention relates to a novel intermediate product and a compound capable of inhibiting a protease encoded by human immunodeficiency virus () IV), especially U.S. Patent No. 5, 4 Synthetic method of compounds disclosed in 13'999 and called " Compound Factory

< Please read the precautions for the memorandum before this page). Packing, 1T, the Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperation, printed compounds J. These compounds are used in the prevention of HIV infection and treatment of mv infection. Pure group (DS) treatment is expensive. More specifically, the present method ㈣ prepares an epoxide intermediate for use as a compound, namely the aforementioned HIV protease inhibitor. In the electrochemical cell, the allyl propanal 2 is electrochemically cyclized by self-salt in a system containing a water-soluble crystal organic co-precipitating agent: J system. Er ^ paper you 4 fortune_ 家家 Γ ^ γΑ4 · --1-i. Ϊ1 594 ^ 112872¾.% ^ Chinese manual revision page (December 88) A7 B7 5th, invention description (propanone 3 2.1 g of propyl bromide 1 2 · 70 g of lithium hexamethyldisilazide (LHMDS) in THF 1.0M solution in tetrahydrofuran (THF) Dissolve acetal in 200 ml of THF and install an addition funnel In a 100 ml 3-neck flask, cool the mixture to -2 ° C and add allyl bromide via a weighing syringe. Move the LHMDS to an addition funnel under nitrogen pressure by cannulation. At 20 Within minutes, make L Η MDS slowly drip into the magnetically stirred reaction mixture. The internal temperature reaches -1 4 ° C, while the cooling bath is -3 0 ° C. At -20 to -1 5 ° C, The mixture was aged for 30 minutes. After adding water (100 ml) and ipac (100) ml, the temperature rose to 5 ° C. The aqueous phase was discarded and 100 ml of 3% aqueous NaCl was added. Wash the organic phase with 2M HC1 '30 ml of brine and 30 ml of 0.5 m sodium bicarbonate. Evaporate the organic phase (55X; 100 Torr) to an oil, add another 40 ml of IPAC, and then The mixture evaporates to an oil. At this time 'crude propyl propyl ketal can be sent directly to the next step, or from 3 〇 · 丨 hexane · IP AC or 3 0: 1 methyl J Cheng hexane -1 PAC The crystal was purified to obtain propyl propyl ketal as a white crystalline solid with a yield of 87%. 105 ml of 200 ml of this 200 ml of THF was placed in: and bubbled with nitrogen for 20 minutes. (Please read the precautions on the back before filling in this page) T * 1- ° The propylpropylation data printed by the main sample of the isomer (62 · 5ΜΗζ) of the Central Cooperative Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 17 1.0 140.4 140.2 129.6 128.6 128.2 126.6 125.6 124.0 96.8 78.9 65.6 47.5 3 8.0 36.1 26.6

134.8 127.1 117.9 38.6 24.1 PPM -22 This paper size is applicable to Chinese solid standard (0 milk) 8 4 specifications (2 丨 0 乂 297) 115948 A7 B7 V. Description of the invention (2

2 Shellfish Consumer Cooperation of the Central Bureau of Specimen Bureau of the Ministry of Economy Degenerative disease agent (eti〇gical agent). This virus was previously known as lav, HTLV-III or ARV. A common feature of antiviral replication is that the precursor polyprotein undergoes a large number of post-translational procedures by virally encoded proteases to produce mature viral proteins required for viral assembly and function. Inhibition of this procedure can prevent the production of normal infectious viruses. 3 For example, 'Cole et al. (KοΜ, NE et al.) In Proc. Nat, l Acad' Sci_} 85, 4686 (1 988), proved that HIV encoding Protease, the transmission of inactivation will cause the production of immature, non-infectious virions. These results show that ΗIV protease inhibition represents a reliable method for the treatment of HIV and HIV prevention or treatment ahiv Nucleus: y: acid sequence shows genes are present in an open reading frame [Ratner, L et al., Nature, 313, 277 (1985)] = amino acid sequence homology provides d-order nesting reverse transcription Evidence of enzyme, endonuclease and HIV protease codes [T0h, η et al., EMBO J_, 4, 1 267 (1985); Power, MD, et al., Science 23 1 1 567 5-Paper Zhang scale is applicable to China National Standards (CNS) A4 specification (ZlOx 297). ----------- Installation ------- Order ------ (Please read the back first & Cautions again. This page) (Α7 Β7

Patent Application No. 85112872 g 1 5 9 4 S Correction Sheet of Chinese Manual (December 88) V. Description of Invention r2) Example 3 Preparation of Amidine 1

(_) _Cis- 丨 _aminoindan_ 2 _ alcohol (884 g '5.93 mol) in a 50 liter round-bottomed flask was dissolved in 17.8 liter of anhydrous Dingcho (= 55 mg / ml) ) [KF stands for Kari Fisher's titration] and the solution of triethylamine (868ml '6.22 mol) is cooled to 15t: the round bottom flask is equipped with a deep thermocouple needle and a mechanical stirrer And nitrogen inlet connector and foamer. Then, within 75 minutes, 3-phenylpropane gas (1000 g, 5.93 moles) was added to 'while maintaining the internal temperature between 14_2 ° C with an ice-water cooling bath. After the addition is complete, place the mixture in! It was aged at 8 to 20 minutes for 30 minutes, and the disappearance of cis-aminoindan-2-ol was examined by HPLC analysis. The reaction was performed by high performance liquid chromatography (H p L c) detection: 25 cm DuPont C8_RX column, 60:40 acetonitrile / 10 mM (KH2P〇4 / K2HP〇4) '1.0 ml / min, injected Column = 20 ml, Detection = 200 nm, Sample Preparation = 500 x Dilution. Approximate residence time: ϋhours-to-minutes (minutes) Component 6 -3 The cis-aminoindanol reaction is treated with pyridine p-toluenesulfonate (24 1 g, 0-96 moles, 0.1 6 equivalents) and dialled Mix for 10 minutes (the pH of the mixture, in the sample volume of 丨 milliliter _____-25-This paper size applies Chinese National Standard (CNS) A4 standard (210X297)) ^ (Please read the precautions on the back before filling (This page)

Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, printed A 7 _B7_ V. Description of Invention (3) (1986); Pearl, LH et al., Nature, 329,351 (198 7)] The final product compounds, including compound J, which can be prepared by the novel intermediates and methods of the present invention are inhibitors of ΗIV protease, and have been disclosed in EP 0,541,168, published on May 12, 1993. Earlier, the synthesis of compound J and related compounds was accomplished by a 1 2 -step procedure: this procedure uses alkylated hydroxy-protected dihydro-5 (S) -hydroxyfluorenyl-3 (2 Η) Furanone, which includes replacing the alcohol leaving group 5 on the alkylated furanone with a hexaargyridine group and then hydrolyzing the coupling product to open the alkanone ring into a hydroxy acid group, and the acid is finally coupled In 2 (11) -¾-yl-Us) -aminoindane. This procedure has been described in EP 0 5 4 1, 1, 6 8 ′. The extreme length (12 steps) of this approach makes this method time consuming and labor intensive, and requires the use of many expensive chemicals and expensive starting materials. Only a few reaction steps and / or more effective medicament routes will provide the desired economy, saving time. 3 Iodolactam of the olefin tertiary ammonium A is converted to iodoimino, which is known to be added with Hydrolysis of the amine B intermediate occurs, and the only isolated product is internally produced C (Reaction formula Avab, see Tamaru, Y et al., J. Am. Chem. Soc., 106, 1079-1 085 (1 984 ); Trost / BM et al., Eds

Comprehensive Organic Synthesis

Strategy & Efficiency in Modern Organic Chemistry Volume 4, Pergamon Press, New York, P.3 98-42 1 = > In this method, it is known that very effective palm transfers will shift from 2-position to 4- Position to obtain a 2,4-cis product with high diastereoselectivity (represented by the corresponding acid D). This paper size applies to Chinese National Standard (CNS) A4 specification (210.X297 mm) (read the precautions on the back before reading ^^ / this page) • Installation line 85 ms ·? 2 profit application 415948 Chinese manual Correction page (December 88) A7 B7

Ministry of Economic Affairs _ Printed by the Central Bureau of Specimen Bakery Consumer Cooperatives 5. Description of the invention () 2 (s) · Third-butylcarboxamide · 4_n_ Boc-hexahydroton spray 4 (1 950 g, 6.83 moles, > 99 5 〇 / 〇ee) (ee = enantiomeric excess) and epoxide 3 (2456 g, 97, 5: 2.5 4S / R epoxide mixture '6.51 Mo Ear) of isopropanol (2-propanol, 18 6 liters) slurry heated to reflux (internal temperature of 8 4-8 5 t); the round bottom flask has four inlets' with a mechanical stirrer, reflux condensing Device, steam bath, Teflon-coated thermocouple and nitrogen inlet. After 40 minutes, a homogeneous solution was obtained. The mixture was heated at reflux for 28 hours. The internal temperature during the reflow period is 8 4-8 5 ° C. The reaction was performed by PLC analysis and detection; 25 cm DuPont C 8-RX column, 6 0.4 acetonitrile / 丨 0 Μ (κη2PO4 / κ2ηρ〇4), ι, 0ml / min, detection = 22nm, sample preparation _ 2 gL, the reaction mixture was diluted to 1 ml with ethyl wax. Approximate retention time (min) Occupation-/4.8 Hexahydrogen (compared to 11 well 4 /8.9 Epoxide 3 15.2 Coupling product 5 2 After 8 hours, the remaining epoxide 3 and coupling product 5 (by H p L c Analysis) were 1.5 area% and 9 1-93 area% respectively. The mixture was cooled to 0-5. 匚 and 20.9 liters of 6N HC1 were added while keeping the temperature below 15t. After the addition was completed, the mixture was warmed To 2 2 t. At this time, it was found that gas release (isobutylene) β aged the mixture at 20 to 2 2 X; 6 hours. The progress of the reaction was analyzed by PLC: the conditions were the same as above. Approximate retention time: —_- 27-This paper size applies Chinese National Standard (Which) 8-4 specification (21 material 297 feet) ----- I I- I-—ί ^^ 1-—-! '_ · ^ 衣 -1— ---I (Please read the precautions on the back of Jing before filling this page) 415948 A7 B7 V. Description of the invention (4

reaction

h2〇 -HNMe2

D In another existing method, acetal is reacted with glycidyl tosylate to form an epoxide in the presence of a strong detection of LHMDS (see Wei Ying / Beta) ------ --- ·., 3 Since the starting material (S) -glycidyl tosylate and the product are both epoxides, the acetal anion will also react with the product epoxide; therefore, about 2 〇 / ό A double addition by-product was formed, and the product epoxide was added in a 71% yield. * After crystallization from NfeOH, additional MTBE recrystallization is required to provide dimer-free epoxide; as a result, the total isolated yield from acetal can be from 56 to 61%. 3 The formation of the dinucleophilic addition product is Problems inherent in electrophilic glycidyl mesylate sulfonate. (S) -Glycidyl tosylate is also a very expensive raw material for the synthesis of Compound J. 1-The paper size is applicable to China Gujia Standard (CNS) Α4 specification (2 丨 0 × 297 mm) ---------- 1 clothing ------- ΐτ ------ m ( Please read the notes on the back of the page first, and then read this page.) The 85th and 12872th prints of the Chinese application for Peel's application were amended by the Central Bureau of Standards of the Ministry of Economy (I2). 415948 A7 B7 Year 5. Inventions Description (25 residence time (min) /7.0 11.9 15.1 cis-amino fragmentation of penultimate compound 6 Coupling product 5 Cool the mixture to 0 ° C, and slowly add 7.5 liters of 50% NaOH to the mixture Ρ Η was adjusted to p Η = 1 1.6, while keeping the temperature below 25 ° C during the addition. The mixture was partitioned with ethyl acetate (40 liters) and water (3 liters). The mixture was searched; mixed The layers were separated. The organic phase (60 liters) was concentrated under reduced pressure, the solvent was converted to DMF and concentrated to a final volume of 0.5 liters (KF = 1.8 mg / ml). 6 in ethyl acetate The yield by HPLC analysis was 86.5%. The penultimate compound 6 in DMF was used directly in the next step without further purification. Isolation 6: l3CNMR (75.4 MH z, CDCI3) d 1 75.2, 1 70.5, 1 40.8, 1 40.5, 1 3 9.9, 1 2 9.1, 128.5, 127.9, 126.8, 126.5, 125.2, 124.2, 73.0, 66.0, 64.8, 62.2, 57.5, 49.5, 47.9 , 46.4, 45.3, 39.6, 3 9.3, 3 8.2, 2 8.9 ° Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -28-n. ^ 1 If---n-li Lf-] 1 III n T _ d _ I j _ ……. * I___ I ______ 0¾ 'T—nn I- *--II-In-I n I -I (Please read the notes on the back before filling out this page} This paper size is applicable to Chinese countries 橾Standard (CNS) A4 grid (210X297 mm) 415948 A7 B7 5. Description of the invention (5 reaction beta

〇 > ^ OTs (S) -_ glycidyl tosylate LHMDS acetal

Reduction LHWDS (please read the precautions on the back V before ^ < this page) Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

In another existing method, the epoxide system consists of allyl acetal 2 and NCS. The paper size is applicable to China National Standards (CNS) A4 specifications (2IOX297 male * > 415948 Article 85112872 Long Profits Zhongjing case Chinese Explanation Ϊ Correction Page (1988 丨 February > A7, B7, Fifth, Invention Description 26-Positive Charge l · Repair · Compound J Monohydrate Preparation Example 5

----------- (Please read the precautions on the back before filling out this page) Ordered by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs ¾ Screen 8 liters of dried DMF (KF < 30 mg / L ) Add to the DMF solution (10.5 liters, KF = 10 mg / ml) of the previous step 6 and heat the mixture in a steam bath under a 30 "Hg vacuum to evaporate the main water and / or any residual isopropyl Alcohol or ethyl acetate solvent. The final concentrate volume is 3 · 5 liters (KF = 1.8 mg / ml), and then triethylamine 86 liters, 20.51 moles) are added to the 25 ° C solution, followed by 3 · Pyridylmethyl chloride hydrochloride (96/0, 1287 g '7.84 moles). The resulting body was heated to 68 ° C. The progress of the reaction was tracked by HPLC using the same conditions as in the previous step. Approximate retention Time: 29-The standard of this paper is 1P national standard (CNS) A4 specifications. Printed Poly A7 ______B7 by the Central Laboratories of the Ministry of Economic Affairs of the People ’s Republic of China. 5. Description of the invention (6) and Nal reaction to obtain iodohydrin. , Which is separated in a separate step to form a strong sulfonium: converted to epoxide 3 See, for example, μ a 1 igres, P. E. et al., Tetrahedron Lett, 36, 21 95 (1 995) 〇 This method is significantly different from these existing methods. In the present invention, the epoxide 3 system is obtained from allyl propionate 2 or sea salt or salt. In a water system containing a water-miscible organic solvent, it is electrolyzed to make it 3. In another alternative embodiment of the present invention, a halohydrin intermediate product 3 a

(X is fluorenyl); It is prepared by replacing water-miscible solvents with water-immiscible organic solvents, that is, propyl acetal 2 is electrochemically oxidized with bromine or iodized salt and water-immiscible solvents. There is only one step in the invention, which can avoid the use of expensive and environmentally harmful agents, such as iodide. Summary of the invention The present invention discloses a method for synthesizing an epoxide with the following chemical formula -------- ^- -----.- IT ------ ^ &lt; Please read the precautions for back Xenon again on this page) {This paper is a standard of Lang Lang Pan (CNS) A4 specification (V. Description of the invention (27 Α7 Β7 Repair time (min.) Of employees' cooperatives in the Central Bureau of Standards of the Ministry of Economic Affairs Component 27 DMF 4 · 2 3 -Pyrimidine methyl gas 4 · 8 Compound J 9 1 Penultimate compound 6 will be added at 6 8 C The mixture was aged until the remaining penultimate compound 6 was <0.3 area% (by ηP LC analysis). The mixture was stirred at 68 ° C for 4 hours, then cooled to 25 ° C, and ethyl acetate (80 Liters) and 24 liters of saturated aqueous NaHC03 distilled water (14 liters) were partitioned. The mixture was stirred at 5 5 r, and each was separated. The ethyl acetate layer was washed three times with water (20 liters) at 5 5 t. The washed ethyl acetate layer was concentrated under atmospheric pressure to a final container volume of 30 liters. When atmospheric pressure was concentrated, water (5 60 ml) was added to the hot solution, and the mixture was cooled to 55 ° C 'and inoculated with compound J monohydrate β to cool the mixture to 4 ° C, and the product was collected by filtration. The product was collected with cold ethyl acetate (2 X 3 L) The product was washed and dried under a household vacuum at 25 ° C to obtain 2905 g (70.7%) of Compound J monohydrate as a white solid. Example 6 Leaf Dagger 2-3rd-Butyl Carboxamide 9

Cl N COOH 8 -30-

The size of this paper applies the Chinese National Standard (CNS) A4 specification (210XW7mm) 1— 1 1-I-HI: / ^ 's ϋ K —i n n τ f 碕 Please read the notes on the back before filling in this page}

415948 at B7 V. Description of Invention (7)

(Wherein X is a halogen group) This method involves the electrochemical oxidation of an allyl acetal reactant with a phosphonium salt in an aqueous system. The 3 product can be used as an intermediate product for the synthesis of renal enzymes or HIV proteases or other protease inhibitors. . . · Slim_write mark A current amperage (Boc) 2〇 (BOC20 or Boc2〇) di-tertiary butyl hydrogen carbonate (+)-CSA (lS)-(+)-10-camphorsulfonic acid DMF Dimethyl hydrazone Et3N triethylamine EtOAc ethyl acetate h hours IPAC or IPAc isopropyl acetate LHMDS lithium hexamethyldisilazide MTBE fluorenyl tertiary butyl ether THF tetrahydrocran-10 -The size of this paper is applicable to Chinese National Standard (CNS) A4 (210X 297mm) I --------- i ----- i1T ------ i (Please read the note on the back first Matters again f'- this page) {Printed by the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economy 28 3.35 kg (27 mol) 3_46 kg (27.2 mol) 9.36 liters (89 mol) 27 liters 1 20 ml 30 liters Economic Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China (Please read the notes on the back before filling in this page)

Revised page of Chinese Specification for Patent Application No. 85112872 (December 88) A? B7 V. Description of the Invention (2-Pyryl Carboxylic Acid (8) Grasshopper Gas Third-Butylamine (KF = 460 μg / ml )

EtOAc (KF = 56 μg / ml) DMF 1-propanol Suspend carboxylic acid 8 in a 72-litre 3-neck flask with 27 litres et 〇ac and i 2 0 ml DMF, while mechanically under nitrogen. Stir 'and cool the suspension to 2 eC. Add grass moth and keep the temperature between $ 8 and $ 8. Add within 5 hours. During the exothermic addition, c 0 and c 0 2 were released. Most of the HC formed is left in solution. Precipitation may occur, which may be the H C1 salt of piracetamyl chloride. The analysis of tritium base gas formation was performed by quenching the reaction anhydrous sample with tert-butylamine. On completion, <0.7% of the acid 8 was left. Thorough analysis of hydrazone formation is important because incomplete reactions can lead to the formation of bis-tertiary-butylpyloramine impurities. The reaction can be detected by HPLC: 25 cm DuPont Zorbax RXC8 column with a flow rate of 1 ml / min and detection at 25 Onm; a linear gradient of 98% 0.1% water H3P04 and 2% CH3CN at 30 minutes Reduced to 50% water H3P04 and 50% CHjCN. Retention time: acid 8 = 107 points, amidine 9 = 28i points. The reaction mixture was aged at 5 C for hours. The resulting slurry was cooled to 0 t, and tertiary-butylamine was added at a rate to keep the internal temperature below 20 ° C as a principle. The addition operation takes 6 hours' because the reaction is extremely exothermic. The third -31-t paper scale to be produced will be in accordance with the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) 41594b V. Description of the invention (8 A7 B7 Mann detailed section in this issue month, its insert Is a method for synthesizing epoxides with the following chemical formula,

C

Including the following steps: a) provide a certain amount of allyl acetal

----------- Private clothes -------, 玎 ------- ^ (Please read the precautions on the back before ^ &gt; + this page} (Ministry of Economy Central Standard隼 扃 Printed by the consumer consumer cooperative I and assemble about 0 '2 main about 2.0 equivalents of 卣 salt' and water-soluble warm co-solvent to make an aqueous mixture; b) at a temperature between about -40 ° C and about 100 ° C Next, the mixture is subjected to a current density between about 〇 1 〇 1 A / cm 2 and about 0.5 A / cm 2; 0 get the desired epoxide. Another specific example of the present invention is a synthesis of the following chemical formula The method of tooth substitution alcohol, ___-11-This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 4 IS8 &amp; 482 patent application Chinese amendment page (88 February 02) A7 B7 V. Description of the Invention (Printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs, placing Pycnogenol-2 -Second-Butylcarboxamide 9 / 1-propanol solution in 5 gallons of autoclaved steel. Catalyst Add and argonize the mixture at 65 ° C and 40 psi (3 atm) H2. After 24 hours the reaction has absorbed the theoretical amount of hydrogen and g C shows 9 &lt; 1%. The mixture is cooled and washed with N2, And use S ο 1K a F The catalyst was removed by filtration. The catalyst was washed with 2 liters of warm 1-propanol. It was found that the use of warm 1-propanol during the washing of the filter cake can improve the process and reduce the loss of product on the cake. Reaction system Detected by GC: 30 m M egab 〇re column, heated from 10 ° C to 160 ° C at 10 eC / min for 5 minutes, and then heated to 10 t / min to 2 5 0 ° C, residence time: 9 = 7.0 minutes, 10 = 9.4 minutes, the reaction can also be detected by TLC 'with E10 A c / M e Ο 5 (50:50) as the solvent and phenanthrone For the developer * The evaporation of the whole part shows that the yield of amidation and hydrogenation is 88%, and the concentration of 10 is 133 g / L. The whole part is evaporated to obtain 10 as a white solid, melting point 1 5 0 · 1 5 1 ° C; 13C NMR (75 MHz 'D20, ppm) 173.5, 59.8, 52.0, 48.7, 45.0, 44.8, 28.7. Example 8 (S) -2 -Third-butylcarboxamide-hexafluorene Pycnogenol (s) -brainsulfonate (S)-11

(+)-CSA

Η .- · 2 (-r) -CSA (Please read the precautions on the back before filling out this page) CONHt-Bu Ή 10 1 11 CONHt-Bu -33-The paper scale is applicable to the Chinese national standard {CNS) A4 specification ( 210x297 mm) 41594b A7 B7 V. Description of the invention (9

Ph

Wherein X is a halogen group; comprising the following steps: a) providing-quantifying allyl propyl ketal having the following structural formula,

(Jing ^ Read and read the precautions again ^^^^ this page)-Install ----. Order printed by the Consumer Cooperatives of the Central Economic and Technical Bureau of the Ministry of Economic Affairs and the amount of between about 0.2 to about 2.0 equivalent The south salt, and the water-immiscible solvent make an aqueous mixture;% b) 'at a temperature between about -4CTC to about 10 (TC, the mixture is subjected to between about 0.01 1 / /: 1112 to about 0. 5/8 / (: 1112 current density: C) to obtain the desired self-fermentation. In the method of the present invention, the halo group is preferably an iodine group or a bromo group β halide salt is preferably from Naί, NaBr, K: I ' K: selected from the group consisting of Br, Et4NI, and Et4NBr. Water-miscible co-solvents, if used, preferably from THF, azulene, DMF, and NMP (N-methyl) bilobital -12 of this paper and its mixture are in accordance with Chinese National Standard (CNS) A4 specification (210 × 297 mm) 418 Shiwu No. 2 profit application Chinese manual amendment page (88 * Γ page (December 88) Α7 Β7 V. Description of the invention (January 31, 2010. Raw materials: 4.10 kg (22.12 moles) in 2 5.5 kg of solvent 10'0 kg (43.2 moles) 12 liters 39 liters 2.4 liters Race 2- Tris-butylcarboxamide-hexahydro 17 bisphrene 10 in 1-propanol solution (s)-(+)-1 0-camphorsulfonic acid 1-propanolacetonitrile water 1-propanol 1-propanol The solution was placed in a 100 liter flask with a batch concentrator. The solution was concentrated to a volume of about 12 liters at 10 mbar and temperature &lt; 25 T. At this point, the product had been removed from the solution by Shen Dian, But when the mixture was heated to 5 0 X, it dissolved into a solution. Analysis of the homogeneous whole showed that the concentration of 10 was 341 g / l. The concentration was determined by HPLC: 25 cm DuPont Zorbax RXC8 column, 1.5 ml / min flow rate and Detected at 210nm, isotopically dissolves (98/2) CH3CN / 0, 1 ° / 〇 hydrous 仏 1> 〇4 ° 10 retention time: 2.5 minutes. Acetonitrile (39 liters) and water (2.4 liters) Add a transparent, light brown solutiona Water content determination of KF titration and iHNMR integration of CH3CN / 1-propanol ratio display, CH3CN / 1 -propanol / H2〇 The ratio is 26/8 / 1.6. The concentration of the solution is 72.2 g / L. Within 30 minutes, at 20 ° C, add (S)-10-camphorsulfonic acid four times. The temperature is at CSA rose to 40 after joining. (:. Number After the bell, i.e. thick white precipitate formed. The white slurry was heated to 7 6 ° C dissolve all solids, then make the light brown solution was cooled to 2 1 ° C within 8 hours. The product precipitated in 6 2 t. Not in 2 1. (: The product will be filtered under aging, and the paper scale is -34-Applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm)} Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 41594b A7 ------- I. __B7 Five 'invention description (10) Three water-immiscible solvents are selected from the group. If used, it is preferably composed of ethyl acetate, isopropyl acetate, related esters, toluene, sulfenyl gas and related halogenated solvents. In the present invention, s is selected. In the present invention, the electrification process of step (b) is preferably performed in an unshunt battery at a temperature range of 1 [about 0 β to about 3 5 t: at a current density of about 0 · 丨a / cm2 is carried out for a period of about 1 hour to about 10 small dollars to complete the reaction 3 more clearly. Another specific example of the present invention is a method for synthesizing an epoxide having the following chemical formula.

It includes the following steps: a) providing an allyl acetal having the following structural formula,

It is made into an aqueous suspension with about 0.2 equivalents to about 2.5 equivalents of NaBr in an acetonitrile / water mixture; the paper size is suitable for household use (CNS) Α4: · (2lGx 297 Gongchu) ----- ---- Equipment ------- 1T ------- m (please read the precautions of ¾ first, then this page) 4? The first page of the patent application (December 88) A7 B7 j ^ Wn__ λ a. May 5th, description of the invention (5 liters of CH3CN / 1-propanol / h2O ratio of 26/8/1. 6 solvent cake was washed. The product was placed in a vacuum oven at 3 5 Drying with N 2 at ° C to obtain 11 of 5.6 kg (39%), which is a white crystalline solid, melting point 28 8-290 t (with decomposition) [a;] D25 = u.9. (C = 0.37, H2〇). &Quot; CNMR (75 MHz, D2〇, ppm) 222.0, 1 64.0, 59.3, 54.9, 5 3.3, 49.0, 48.1, 43.6, 43.5, 43.1, 40.6, 40.4, 28.5, 27.2, 25.4, 19_9, 19.8. According to the following enantio-HPLC analysis: 1 1 aliquots (33 mg) were suspended in 4 ml of EtOH and 1 ml was added to Et3N, and the ee of the product was 95%. B 0c 2 0 (11 mg ) Add and age the mixture for 1 hour. Remove the solvent completely in vacuo and dissolve the residue in about 1 ml of Eto c. After passing through a pasteur pipet equipped with Si02, EtOAc was used as the eluent. The evaporated product portion was dissolved in hexane at about 丨 mg / 1ml Medium. Daicel Chiracell AS column was used to separate the enantiomers, using Jihu / IPA (97 ·· 3) solvent system, the flow rate was 1 ml / min and detected at 22 8nm. Retention time; S enantiomer = 7.4 Points, R = 9.7 points. Example 9. Preparation of (S) -2-Third-butylcarboxamide-4-Third-butoxycarbonyl- from -Salt 1 1 (Please read the notes on the back of Jing first (Fill in this page again.) Printed hydrogen p printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs 4

* 2 (+)-CSA (b〇c) 2〇 CONHi-Bu 11

Boc NN ..... N CONHt-Bu H 4 35-This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 41594b A7 B7 V. Description of the invention (11) b) In unshunted batteries, At a temperature of about 2 CTC, the suspension is subjected to a current density of about 0.1 A / cm2 for about 1 hour to about 10 hours; 〇 to obtain the desired epoxide. Another specific example of the present invention is a method for integrally synthesizing a self-substituted alcohol having the following chemical formula,

Wherein X is a gas-based or bromo-based group; comprising the following steps: a) providing an equivalent of propylpropylacetal having the following structural formula,

Ph

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before ^ &lt; this page), and it contains about 0.2 equivalents to about 2.5 equivalents with ethyl acetate or isopropyl acetate. I A / cm2 的 时 温度 为时 1 In a non-shunt battery, at a temperature of about 20 ° C, the dual-phase system is made into a two-phase system; Hours to about 10 hours; -14-This paper size applies Chinese National Standard (CNS) A4 specifications (210X 297 mm) for profit application case Weiyongzheng ## 正 页 (December 88) A7 B7 V. Invention Description (33

Kc: 5.54 kg (8.53 moles) printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs 8.6 kg (8.5 3 moles) 5.95 liters (42.6 moles) 55 liters 2 liters Next, add three raw materials at 25 ° C

(S) .2 · Di-tri-butylamine-hexahydro p ratio Gengshuang (S)-(+)-CSA salt 1 1,95% ee Tri-third-butyl hydrogen carbonate E13 N

EtOH Punctilous 200 ^

EtO Ac EtOH was added to the (S) -CSA salt 11 and ethylamine in a 100 liter 3-necked flask under N2. The solid dissolved immediately when Et3N was added. B 0 c 2 0 was dissolved in E t 0 A c and added to the addition funnel. The E10 A c solution of B 0 c 2 0 was added at a rate capable of maintaining the temperature below 25 ° C. Adding work takes 3 hours. After the addition of the B 0 c20 solution was complete, the reaction mixture was aged for 1 hour. The reaction can be detected by PLC: 25 cm DuPont Zorbax RXC8 column, 1 ml / min flow rate and detected at 2 28 nm, allelic dissociation (5 0/5 0) CHs CN / 0.1M KH2P〇4 to NaOH was adjusted to pH = 6.8. Dwell time of 4 = 7.2 minutes. Enantiomeric analysis was performed using the same system as the previous steps. The reaction can also be detected by T L C with 100% E t Ο A c as the solvent. (R r = 0.7). It is then concentrated in a batch concentrator under vacuum at 10 mbar to about 10 liters at an internal temperature &lt; 20 ° C. The solvent conversion was completed by slowly putting 20 liters of E t Ο A c and the solution was concentrated to about 10 liters. The reaction mixture was washed with 60 liters of E tO A c into the extractor. The organic phase was washed with 16 liters of a 5% Na2C03 aqueous solution, 2 X 100 liters of Di water, and 2 X 6 liters of a saturated sodium chloride aqueous solution. The combined aqueous washing solution is back-extracted with 20 liters of EtO Ac, while the organic phase is saturated with 2 X 3 liters of water and 2 X 4 water -36. This paper size applies to national standards (CNS &gt; A4 specifications (2 丨 0X297 mm) ) (Please read the precautions on the back before filling this page)

41594b A7 ----------- B7 V. Description of the invention (u) c) The desired tooth alkanol 3 The present invention can be divided into two groups: one by one, one by &amp;, one by ring Synthesis of oxides and synthesis of Mt alcohols. The two processes are substantially parallel, except for the solvent used in the reduction of the step snails. [In the epoxidation process, water is used-this is ig ~ agent ', and _generation enzyme 出 人 目 _ 丨 m wπ Use a water-immiscible solvent. Synthetic point of star compounds '' The synthesis of epoxides in this month will be explained by the following reaction formula: Reaction Formula Gama-

The reaction conditions for the formation of allyl oxide are the use of separated or unseparated electrochemical cells with an anode and a cathode that are stable to the reaction conditions. Anode and cathode materials include, but are not limited to, graphite 'platinum' silver, nickel, stainless steel, zinc, zinc dioxide or other special materials, such as titanium dioxide coated or stainless steel coated. A preferred electrochemical cell is During the electrification process of the shunt battery 3, the current density is maintained between about 0.01 A / cm2 and about 0.5 A / cm2, preferably about 0.01A / Cm2. 3 The choice of current density depends on the paper size Applicable in the 11_ house standard rate (CNS) A4 specification (21GX297 public voice) — i ------- install --- 1 --- order ------ good (please first * please breathe please Zhi. ¾ Italian Matters 戽 ^^ 本 育) (Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, printed by the Ministry of Economic Affairs and the Central Standards Bureau of the Ministry of Economics, Λ4 Consumer Cooperatives ^ 41594b A7 ----- B7 V. Description of the Invention (13) (Type, its shape 'the shape of the electrochemical cell and the distance between the anode and the cathode are sufficient = reaction' The current density is preferably kept constant. The electricity 1 generally rises during the reaction 'but usually stays in a safe range Within, for example, about 伏 volts s. Xingfujia halogenating agents include halogen salts of aqueous systems, such as bromide or iodide of Na, K, UU or Mg. Other preferred exhaustion Includes a fourth ammonium salt, such as Ε′ΝΒΓ. The good halogen salt is the brook or iodide of Na, κ. The amount of the halogen salt can be from about 02 to about 2 Q or more of propylpropyl ketal 2. Equivalents include reaction conditions including allyl acetal, acetating agent, and water-miscible solvent, such as caustic solution, suspension, or other two-phase system. Appropriate water-miscible. Solvents include but are not limited to THF, acetonitrile, DMF or NMP (N-methylpyrrolidone) 3 A group of preferred reaction conditions for the synthesis of epoxide is a suspension in a mixture of acetonitrile and water = temperature range is between about -4 &lt; rc and Between about 100 ° C, but preferably between about 0 ° C: and about 35 ° C = 'Typical time range of reaction element formation is between about 1 hour and about {0 hour 3 reaction time required to react The end depends on the size of the electrode and the shape of the electrochemical cell. 9 The combination of halogenated alcohols can be used to synthesize the stable intermediate product halogenated alcohols 3 a _____ 16 _ This paper size is applicable to Chinese national standards隼 (CNS) A4 is now available (21〇 乂 297mm) --.------- ^ ------- 1T ------- {Please read the notice of the back first '' again P) / 415 948 Ministry of Economic Affairs Bureau of the Central-like quasi-employees consumer cooperatives printed A7 B7 V. description of the invention (I4) reactive ask him

The reaction conditions for the formation of dipropylene copper 2 3 a epoxide are the use of separated or unseparated electrochemical cells with an anode and a cathode that are stable to the reaction conditions. Anode and cathode materials include, but are not limited to, graphite, Zhao, platinum, short, nickel, stainless steel, zinc, titanium dioxide, or other special materials, such as coated with titanium dioxide or coated with steel, a preferred electrochemical The battery is an unshunted battery 3 During the electrification process, the current density is maintained between about 0.001 A / cm2 and about 0.5 A / cm2, preferably about 0.1 A / cm2. The choice of current density depends on the type of electrode, its shape, the shape of the electrochemical cell, and the distance between the anode and the cathode. The voltage generally rises during the reaction, but the mother often stays within a safe range, for example, about 0.1 _ 10 volts. Preferred halogenating agents include halides of aqueous systems, such as bromides or iodides of Na, K, Li, Ca or Mg. Other preferred salts include a fourth ammonium salt, such as EUN Br. The most preferred halide is n a 'K bromide or broken poplar. The amount of halide salt can vary from about 0.2 to about 2.0 or more equivalents of allylpropane-2. The reaction conditions for the synthesis of halogenated alcohols include propylpropylacetal, dentition agent and __ -17-This paper size applies to China National Standard {CNS &gt; A4 (210 × Μ? Mm) ------------- Shenyi --------- 11 --- --- i (Please read the precautions on the back and then this page). (Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 415946 A 7 _______B7____ V. Description of the Invention (I5) Water-insoluble solution and suspension Or other two-phase systems s suitable water-immiscible solvents include, but are not limited to, ethyl acetate, isopropyl acetate, butyl acetate and related esters, and toluene 'methylene gas and related halogenated solvents, draw alcohols A group of preferred synthetic reaction conditions for 3a is a two-phase system containing ethyl acetate and Na I in water. The temperature range for the synthesis of halogenated alcohols 3 a by electrochemical treatment is between about -40aC and about 100 ^: Time, but preferably between about 0.0 and about 35. (: between:> typical time range of reaction element formation is between about 1 hour and about 100 hours) 3 reaction is complete The time required depends on the size of the electrode and the shape of the electrochemical cell. The various processes and intermediate products of the present invention can be used to prepare the final product compound, which can be used to inhibit HIV protease and prevent or treat human immunodeficiency virus infection and treatment. The resulting pathological conditions, such as AIDS, treatment of AIDS, or prevention or treatment of HIV infection, its definition includes, but is not limited to, treatment of a wide range of HIV infection states: AIDS, ARC (AIDS-related syndrome), symptomatic and asymptomatic, And actual or possible exposure to 下 ¥ 3 For example, the final product compounds that can be made from the process of the invention and intermediates can be used to treat HIV infections that were suspected of being exposed to HIV in the past, such as exposure to blood transfusions, organ transplants, body fluid exchange, A bite that is not infected by acupuncture or exposed to the patient's blood during surgery IV infection. The final product HIV protease inhibitor can also be used to prepare and perform screening for antiviral compounds. For example, the final product compound can be used to isolate enzyme processes It is an excellent tool for the detection of stronger antiviral compounds. Furthermore, these compounds can be used for, For example, through competitive inhibition to establish or determine the position of other antiviral binding to HI V protease. Therefore, according to the process of the present invention-«_________-18 ~ the paper scale applies the Zhongguanjiaxinxin (CNS) M specification (210 × 297) '-~~----------- install ------- order ------- East (please read the precautions on the back and then f page) ί 415948 Central Ministry of Economic Affairs A7 in Quasi-office Consumer Cooperatives V. Description of the invention (the final product compounds made from intermediate and intermediate products are commercially available products for these uses) HIV protease inhibitor compounds made from the intermediate products and processes of the present invention It has been disclosed in EP 0 541,164 »HIV protease inhibitory compounds may comprise a drug-reducing carrier and a therapeutically effective amount of a compound or a therapeutically acceptable pharmaceutical composition thereof for administration to a patient in need of such treatment. Ε ρ 541,164 reveals suitable pharmaceutical formulations, routes of administration, salt forms and dosages of the compounds. 5 The compounds of the present invention may have asymmetric centers, with racemates, racemic mixtures, and individual diastereomers. Constituents or enantiomers exist, and all isomeric forms are included in the present invention. 'When any variable, such as X, exists more than once in any component, its definition of each occurrence is independent of the definition of all other existences, and at the same time, the combination of substituents and / or variables can only be generated in such combinations 3α is only allowed when used to stabilize compounds, as used herein, unless otherwise noted. "" Funyl "means fluoro, bromo, and iodo. Representative experimental procedures using novel methods are described in detail below. These procedures are only It is illustrative and should not be construed as a limitation on the method of the present invention. Example 1 Electrochemical oxidation A. Electrochemical ring gasification This paper is applicable to China National Standard (CNS) A4 specification (21GX-297 mm /

5. Description of the invention (π

Allyl ketal 2 allyl ketal creek steel

H2〇 ch3cn THF A7 B7 electrochemical cell

NaBr H2〇, thf, ch3cn

Epoxide 3 5-00 g (13.8 mmol) 2 · 45 g (24 mmol) 50 ml 50 ml 20 ml of pharmaceuticals and solvents are made by installing a magnetic stirrer and graphite and carbon drum The electrode is mixed in a jacketed container. A constant current of 0.5 A was applied, and the container was kept at 200. After the reaction was completed, the organic solvent was evaporated and the product was extracted into MTBE. After washing with water, the MTBE was evaporated, and then Residual product crystallized to obtain 4.24 g (81%) of epoxide as a white solid, which was electrolyzed with β-fluorenol to form '---------- ^ ------. 玎- ----- &quot; (Please read the two notes before reading this page} (Printed by the Consumers' Cooperative Work of the Central Standards Bureau, Ministry of Economic Affairs, 9 ·

Epoxide 3a -20-This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm &gt; 12872 Patent Application Chinese Specification Correction Page (SJJ December) A7 B7 V. Description of the invention (80) Σΐ4 allyl copper 2 allyl acetal * canonical sodium H 2 0 isopropyl acetate epoxide 3 a 5. 00 g (13.8 mmol) (24 mmol) 50 0 ml 30 The milliliter of medicament and solvent are mixed in a jacketed container equipped with a stirrer and an electrode made of graphite and carbon. A constant current of 0.5 A is applied and the container is kept below 20. After the reaction is completed, the product 3a is separated. The carbon 3 NMR data (75.5 MHZ at CDC6) are as follows: Epoxide 3: m, 140, 140, 139, 129, 128, 128, 127,] 26, 125, 1 24, 96, 78, 65, 5 1 , 47, 45, 4 1, 37, 3 6, 27 and 24 Epoxides 3 a 172, 140, 140, 139, 129, 128, 128, 127 '127, 125, 124, 97, 78, 67, 65 , 44, 40, 39, 36, 27, 24, and 16 (Please read the notes on the back before filling out this page) Τ, -ιρ Example of consumer cooperation cooperation between the Central Bureau of Standards of the Ministry of Economy and Du Yinju 2

C surplus

-21-This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) Ϊ1 594 ^ 112872¾.% ^ Chinese manual correction page (December 88) A7 B7 5th, invention description (propanone 3 2.1 g of propyl bromide 1 2 · 70 g of lithium hexamethyldisilazide (LHMDS) in THF 1.0M solution in tetrahydrofuran (THF) Dissolve acetal in 200 ml of THF and install an addition funnel In a 100 ml 3-neck flask, cool the mixture to -2 ° C and add allyl bromide via a weighing syringe. Move the LHMDS to an addition funnel under nitrogen pressure by cannulation. At 20 Within minutes, make L Η MDS slowly drip into the magnetically stirred reaction mixture. The internal temperature reaches -1 4 ° C, while the cooling bath is -3 0 ° C. At -20 to -1 5 ° C, The mixture was aged for 30 minutes. After adding water (100 ml) and ipac (100) ml, the temperature rose to 5 ° C. The aqueous phase was discarded and 100 ml of 3% aqueous NaCl was added. Wash the organic phase with 2M HC1 '30 ml of brine and 30 ml of 0.5 m sodium bicarbonate. Evaporate the organic phase (55X; 100 Torr) to Add another 40 ml of IPAC, and then evaporate the mixture to oil. At this time, 'crude propyl propyl ketal can be sent directly to the next step, or from 3 〇 · 丨 burned · IP AC or 3 0: 1 Methyl J was purified by crystallization of hexane-1 PAC to obtain propylpropanal as a white crystalline solid with a yield of 87%. 105 ml of 200 ml of this 200 ml of THF was placed in: and bubbled with nitrogen. Fenzheng vr'-Ί— (Please read the notes on the back before filling in this page) T * 1- ° Member of the Central Bureau of Prospecting, Ministry of Economic Affairs, Consumer Cooperative, printing of major rotational isomers (62 · 5ΜΗζ)) Propyl-propion data 17 1.0 140.4 140.2 129.6 128.6 128.2 126.6 125.6 124.0 96.8 78.9 65.6 47.5 3 8.0 36.1 26.6

134.8 127.1 117.9 38.6 24.1 PPM -22 This paper size is applicable to Chinese solid standard (0 milk) 8 4 specifications (2 丨 0 乂 297) 415946 A7 B7 V. Description of the invention (2〇_propylpropyl acetal synthesis

N 〇 Binghua discretion [321.42] 巳 Γ.

[120.98]

LDS THF ..- 15 to 20 ° C

[361.49] 200 grams.-0.617 moles 77.6 grams 53.6 ml 0.64 ^ mole 5 18 ml '0.684 moles 35.73 g 0.186 moles printed by acetal allyl bromide LDS: THF 1.32M citrate #acid THF sieve dry 1.43 liters of water 1.05 liters 0.3 M H2S04 1.18 liters 6% NaHC03 1.18 liters of IPAc Sieve dry at 1-25 liters in a nitrogen atmosphere at 25 ° C (sieve ddecOTHFCiCF: 11 mg / L) and stir with a machine. The KF of the resulting solution was 40 mg / L at this time. The solution was subjected to three alternate emptying / nitrogen cleaning cycles to remove the dissolved oxygen from the solution. Allyl bromide was added to the THF solution. The resulting KF was 75 mg / liter. Pre-LDS solution KF level is 200 mg / L and 10% excess alkali is available. -23-This paper standard is applicable to China National Standard (CNS) A4 specification (210 × 297 male |) ----- ----- Equipment ---------- Order ------ 朿 {Read Kr, read the back, the precautions, and then ^ r this page) ί 415946 A 7 a -----__ JZ___ grams, invention description (U) Typical complete conversion (&gt; 99.5%) s. Then, the solution was cooled to -20 ec, and hexamethyldisilazide butyl HF solution (LDS [32M) was added to allyl> The odor drop 'addition rate is to maintain the reaction temperature at _201. The addition of LD s takes 30 minutes. 3 The mixture is aged at _5 to 2 (rc, and terminated at a conversion rate of> 99%. The reaction was analyzed by H p L c for ai hours, and the reaction had reached> 99.5% conversion. By adding citric acid (3 :). 7 g, 0.186 mole) solution dissolved in 1 86 ml of butyl HF To terminate the reaction. After the addition of citric acid, the mixture was aged at 5 T for 30 minutes. Concentrate the mixture to about 30% of the original volume under reduced pressure (about 2 8 · · fruit column), while maintaining the container temperature at 1 15 ° C and collect 900 ml of distillate s in a dry ice cooling trap and then switch the solvent. 'Use A total of 27 liters of isopropyl acetate (I pac) _, while maintaining the distillation under reduced pressurea. When 1 HNMR (see the analysis report of the GC method) analysis shows that <1 mole% THF is left, the solvent is stopped Conversion. The maximum temperature during the distillation must not exceed 35 ° C. The crude mixture in IPAc was washed with 1.05 liters of distilled water, 0.3 liters of 0.3 M sulfuric acid, and 1.1 liters of 6% aqueous sodium hydrogen carbonate solution. After washing, the volume of the organic phase was 1.86 liters. Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumption Co-operation. ----.- IJ {Please read the notes on the back and read this page first, then this page) The pH of the mixture after three times of washing with aqueous solution is 6.5, 1.3 and 8.5. At this time, the HPLC analysis of the mixture showed that the analytical yield of acetal · was 93-94%. The ratio of allyl ketal to epi-allyl ketal was 96: 4 by HPLC analysis (same conditions as above). At this time, the GL analysis showed that the by-products of hexamethyldisilazane had been completely removed during the treatment. ”The paper size is applicable to the Chinese National Standard (CNS) Α4 size (210X 297 mm) Α7 Β7

Patent Application No. 85112872 g 1 5 9 4 S Correction Sheet of Chinese Manual (December 88) V. Description of Invention r2) Example 3 Preparation of Amidine 1

(_) _Cis- 丨 _aminoindan_ 2 _ alcohol (884 g '5.93 mol) in a 50 liter round-bottomed flask was dissolved in 17.8 liter of anhydrous Dingcho (= 55 mg / ml) ) [KF stands for Kari Fisher's titration] and the solution of triethylamine (868ml '6.22 mol) is cooled to 15t: the round bottom flask is equipped with a deep thermocouple needle and a mechanical stirrer And nitrogen inlet connector and foamer. Then, within 75 minutes, 3-phenylpropane gas (1000 g, 5.93 moles) was added to 'while maintaining the internal temperature between 14_2 ° C with an ice-water cooling bath. After the addition is complete, place the mixture in! It was aged at 8 to 20 minutes for 30 minutes, and the disappearance of cis-aminoindan-2-ol was examined by HPLC analysis. The reaction was performed by high performance liquid chromatography (H p L c) detection: 25 cm DuPont C8_RX column, 60:40 acetonitrile / 10 mM (KH2P〇4 / K2HP〇4) '1.0 ml / min, injected Column = 20 ml, Detection = 200 nm, Sample Preparation = 500 x Dilution. Approximate residence time: ϋhours-to-minutes (minutes) Component 6 -3 The cis-aminoindanol reaction is treated with pyridine p-toluenesulfonate (24 1 g, 0-96 moles, 0.1 6 equivalents) and dialled Mix for 10 minutes (the pH of the mixture, in the sample volume of 丨 milliliter _____-25-This paper size applies Chinese National Standard (CNS) A4 standard (210X297)) ^ (Please read the precautions on the back before filling (This page)

Printed by the Central Standards Bureau of the Ministry of Economic Affairs, the Shellfish Consumer Cooperative, printed by the Central Standards Bureau of the Ministry of Economic Affairs, printed by the Consumers ’Cooperative, 41594b A 7 B7 V. Description of the invention (23) After dilution with water, it is between 4.3-4.6) = then add 2 -Methoxypropene (1.27 liters, IS. 24 moles, 2.2 equivalents) and the reaction was heated to 38-4 ° C for 2 hours. Example 4 Preparation of penultimate compound 6

This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) ϋ IT ------- I —1 In --- T n HI HI ____ #; 'US Ί / (Please read back Yttrium Note on this page) f No. 85 ms ·? 2 profit application 415948 Chinese manual revision page (December 88) A7 B7

Ministry of Economic Affairs _ Printed by the Central Bureau of Specimen Bakery Consumer Cooperatives 5. Description of the invention () 2 (s) · Third-butylcarboxamide · 4_n_ Boc-hexahydroton spray 4 (1 950 g, 6.83 moles, &gt; 99 5 〇 / 〇ee) (ee = enantiomeric excess) and epoxide 3 (2456 g, 97, 5: 2.5 4S / R epoxide mixture '6.51 Mo Ear) of isopropanol (2-propanol, 18 6 liters) slurry heated to reflux (internal temperature of 8 4-8 5 t); the round bottom flask has four inlets' with a mechanical stirrer, reflux condensing Device, steam bath, Teflon-coated thermocouple and nitrogen inlet. After 40 minutes, a homogeneous solution was obtained. The mixture was heated at reflux for 28 hours. The internal temperature during the reflow period is 8 4-8 5 ° C. The reaction was performed by PLC analysis and detection; 25 cm DuPont C 8-RX column, 6 0.4 acetonitrile / 丨 0 Μ (κη2PO4 / κ2ηρ〇4), ι, 0ml / min, detection = 22nm, sample preparation _ 2 gL, the reaction mixture was diluted to 1 ml with ethyl wax. Approximate retention time (min) Occupation-/4.8 Hexahydrogen (compared to 11 well 4 /8.9 Epoxide 3 15.2 Coupling product 5 2 After 8 hours, the remaining epoxide 3 and coupling product 5 (by H p L c Analysis) were 1.5 area% and 9 1-93 area% respectively. The mixture was cooled to 0-5. 匚 and 20.9 liters of 6N HC1 were added while keeping the temperature below 15t. After the addition was completed, the mixture was warmed To 2 2 t. At this time, it was found that gas release (isobutylene) β aged the mixture at 20 to 2 2 X; 6 hours. The progress of the reaction was analyzed by PLC: the conditions were the same as above. Approximate retention time: —_- 27-This paper size applies Chinese National Standard (Which) 8-4 specification (21 material 297 feet) ----- I I- I-—ί ^^ 1-—-! '_ · ^ 衣 -1— ---I (Please read the precautions on the back of Jing before filling out this page) Article 85 丨 12872¾ Amendment to the Chinese Manual of Bailey's Application (Tart Year IFebruary) 415948 A7 B7 Year V. Description of Invention (25 Detention Time (Minutes ) /7.0 11.9 15.1 The penultimate compound of the cis-amino group full of enzyme 6 Coupling product 5 Cool the mixture to 0 ° C and slowly add 7.5 Liter 50% NaOH, adjust the ρ 混合物 of the mixture to p Η = 1 1.6, while keeping the temperature below 25 ° C during the addition. The mixture was ethyl acetate (40 liters) and water (3 liters) ) Partition. The mixture was searched; the layers were mixed and separated. The organic phase (60 liters) was concentrated under reduced pressure, the solvent was converted to DMF, and concentrated to a final volume of 1.0 liter (KF = 1.8 mg / ml). ). 6 The yield of HPLC analysis in ethyl acetate was 86.5%. The penultimate compound 6 in DMF was used directly in the next step without further purification. Isolation 6: l3CNMR (75.4 MHz, CDCI3) ) d 1 75.2, 1 70.5, 1 40.8, 1 40.5, 1 3 9.9, 1 2 9.1, 128.5, 127.9, 126.8, 126.5, 125.2, 124.2, 73.0, 66.0, 64.8, 62.2, 57.5, 49.5, 47.9, 46.4, 45.3, 39.6, 3 9.3, 3 8.2, 2 8.9 ° Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -28-n. ^ 1 If---n-li Lf-] 1 III n T _ d _ I j _ ……. * I___ I ______ 0¾ 'T—nn I- *--II-In-I n I -I (Please read the precautions on the back before filling this page} This paper size applies to China National Standards (CNS ) A4 Grid (210X29 7mm) 415948 The 85112872 Long Profit Zhongjing Case Chinese ExplanationΪRevision Page (88 丨 February &gt; A7 B7 years V. Description of the Invention 26-Positive Charge l · Repair · Preparation of Compound J Monohydrate Example 5

----------- (Please read the precautions on the back before filling out this page) Ordered by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs ¾ Screen 8 liters of dried DMF (KF &lt; 30 mg / L ) Add to the DMF solution (10.5 liters, KF = 10 mg / ml) of the previous step 6 and heat the mixture in a steam bath under a 30 "Hg vacuum to evaporate the main water and / or any residual isopropyl Alcohol or ethyl acetate solvent. The final concentrate volume is 3 · 5 liters (KF = 1.8 mg / ml), and then triethylamine 86 liters, 20.51 moles) are added to the 25 ° C solution, followed by 3 · Pyridylmethyl chloride hydrochloride (96/0, 1287 g '7.84 moles). The resulting body was heated to 68 ° C. The progress of the reaction was tracked by HPLC using the same conditions as in the previous step. Approximate retention Time: 29-The standard of this paper is 1P National Standard (CNS) A4 Specification V. Description of invention (27 Α7 Β7 Repair time (minutes) for the printing of employee cooperatives by the Central Bureau of Standards of the Ministry of Economic Affairs Component 27 DMF 4 · 2 3- Pyridylmethyl gas 4 · 8 Compound J 9 1 Penultimate compound 6 The mixture was aged at 6 8 C until residual The second compound 6 is &lt; 0.3 area% (by ηP LC analysis). The mixture is stirred at 68 ° C for 4 hours, then cooled to 25 ° C, and ethyl acetate (80 liters) and 24 liters are used. A mixture of saturated aqueous NaHC03 distilled water (14 liters) was partitioned. The mixture was stirred at 5 5 r and the layers were separated. The ethyl acetate layer was washed three times with water (20 liters) at 5 5 t. The washed The ethyl acetate layer was concentrated at atmospheric pressure to a final container volume of 30 liters. When the atmospheric concentration was concentrated, water (5 60 ml) was added to the hot solution, and the mixture was cooled to 5 5 ° C 'and compound J alone was used. The hydrate was inoculated with β to cool the mixture to 4 ° C, and the product was collected by filtration. The product was washed with cold ethyl acetate (2 X 3 liters) and dried in a household vacuum at 25 ° C to obtain 2905 g (70.7%) of the compound J monohydrate as a white solid. Example 6

Cl N COOH 8 -30-

The size of this paper is applicable to Chinese National Standard (CNS) A4 (210XW7mm) 1— 1 1-I-HI: / ^ 氏 ϋ K —inn τ f 碕 Please read the notes on the back before filling in this page} 28 3.35 kg (27 mol) 3_46 kg (27.2 mol) 9.36 liters (89 mol) 27 liters 1 20 ml 30 liters Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling in this page)

Revised page of Chinese Specification for Patent Application No. 85112872 (December 88) A? B7 V. Description of the Invention (2-Pyryl Carboxylic Acid (8) Grasshopper Gas Third-Butylamine (KF = 460 μg / ml )

EtOAc (KF = 56 μg / ml) DMF 1-propanol Suspend carboxylic acid 8 in a 72-litre 3-neck flask with 27 litres et 〇ac and i 2 0 ml DMF, while mechanically under nitrogen. Stir 'and cool the suspension to 2 eC. Add grass moth and keep the temperature between $ 8 and $ 8. Add within 5 hours. During the exothermic addition, c 0 and c 0 2 were released. Most of the HC formed is left in solution. Precipitation may occur, which may be the H C1 salt of piracetamyl chloride. The analysis of tritium base gas formation was performed by quenching the reaction anhydrous sample with tert-butylamine. On completion, <0.7% of the acid 8 was left. Thorough analysis of hydrazone formation is important because incomplete reactions can lead to the formation of bis-tertiary-butylpyloramine impurities. The reaction can be detected by HPLC: 25 cm DuPont Zorbax RXC8 column with a flow rate of 1 ml / min and detection at 25 Onm; a linear gradient of 98% 0.1% water H3P04 and 2% CH3CN at 30 minutes Reduced to 50% water H3P04 and 50% CHjCN. Retention time: acid 8 = 107 points, amidine 9 = 28i points. The reaction mixture was aged at 5 C for hours. The resulting slurry was cooled to 0 t, and tertiary-butylamine was added at a rate to keep the internal temperature below 20 ° C as a principle. The addition operation takes 6 hours' because the reaction is extremely exothermic. The third -31-t paper scale to be produced is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) A7 B7 415348 29 V. Description of the invention (-Butyl ammonium hydrochloride—small part of self-reaction Clear as a fluffy white solid. The mixture was aged at 18 ° C for another 30 minutes. The precipitated ammonium salt was removed by filtration. The filter cake was washed with 6 # of the combined organic phase and washed with 6 liters. '/ oMaHCCh and 2 X 2 liters of saturated aqueous NaCl wash strip 3 # 2〇qDarc〇G60 carbon treated organic phase, and filtered with solka Fik, the filter cake was washed with 4 liters of EtOAc 3 U ------ Some purple color of the product was removed in place. The EtOAc solution of 9 was concentrated to its original mass at 10 mbar. 25% of the volume 3 was added 30 liters of 1-propanol, and the distillation was continued until the final volume reached a liter. , EtOAc is under the detection limit of HNMR (&lt; 1%). The internal temperature of this solvent change is &lt; 3 (TC. 3'-propanol / EtOAc solution is refluxed for several days under atmospheric waste. Stability. 'Evaporate the whole fo' to obtain a brown solid 'Falling point 87-88 ° C. 13CNMIl ^ 75 MHz, CDC13, ppm) 161.8, 146.8, 145.0, 143.8, 142.1, 5 1 .0, 28.5 »Example 7 Racemic-1-tertiary-butyl-induced δ1: amine-hexahydro ratio • 丼 1 〇 ----—_ Printed by H2 / Pd ( OH) 2

CONHt-Bu 'N Eight CONHt-Bu 9 Raw leaf fc 11 Well-2-Third-Butyl dichloramide 9 2.4 kg (ι34 mol) of _ propanol solution 1 2 liters 20% P d (0 H) 2 / C 1 6 Weight ° /. Water 1 4 4 g. -32-This paper size applies the Chinese National Standard (CNS) Α4 is present (210x 297 public variable) 4 IS8 &amp; 482 patent application Chinese amendment page (88 February 02) A7 B7 V. Description of the invention (Ministry of Economy Printed by the Consumer Cooperatives of the Central Bureau of Prototype Bureau Put Pycnogenol-2-Second-Butylcarboxamide 9 / 1-propanol solution into 5 gallons of autoclaved steel. Add the catalyst at 65 ° C and 40psi (3 atmospheres) The mixture was argonized under H2. After 24 hours, the reaction had absorbed a theoretical amount of hydrogen, and g C showed 9 &lt; 1%. The mixture was cooled, washed with N2, and washed with S 1K a FL 〇c The catalyst was removed by filtration. The catalyst was washed with 2 liters of warm 1-propanol. It was found that the use of warm 1-propanol in the washing of the filter cake can improve the process and reduce the loss of product on the cake. The reaction is detected by GC Measurement: 30 m M egab 〇re column, heated at 10 eC / min from 1 0 0 ° C to 16 0 ° C 'Hold for 5 minutes, and then heated at 10 t: / min to 2 5 0 ° C, retention time: 9 = 7.0 minutes, 10 = 9.4 minutes, the reaction can also be detected by TLC 'with E10 A c / M e Ο 5 (50:50) as the solvent and phenanthrone as the imaging Agent * Whole The evaporation showed that the yield of amidation and hydrogenation was 88%, and the concentration of 10 was 133 g / L. The whole portion was evaporated to give 10 as a white solid, melting point 15 0 · 15 1 ° C l3CNMR (75 MHz 'D20, ppm) 173.5, 59.8, 52.0, 48.7, 45.0, 44.8, 28.7. Example 8 (S) -2 -Third-butylcarboxamide-hexapyrine bis (s)- Saponin (S)-11

(+)-CSA

Η .- · 2 (-r) -CSA (Please read the precautions on the back before filling out this page) CONHt-Bu Ή 10 1 11 CONHt-Bu -33-The paper scale is applicable to the Chinese national standard {CNS) A4 specification ( 210x297 mm) Revised Chinese Manual for Profit Application No. 418 No. 2 (88 * Γ pages (December 1988) Α7 Β7 V. Description of the invention (January 31st, V2 · Raw materials 4.10 kg (22.12 moles) 10'0 kg (43.2 mol) in 2 5.5 kg of solvent 12 liters 39 liters 2.4 liters of racemic 2-tertiary-butylcarboxamide-hexahydro 17 bicorphine 10 in 1 -propanol solution (s) -(+)-10- camphorsulfonic acid 1-propanolacetonitrile water Place the amine 10-propanol solution in a 1000 liter flask with a batch concentrator. The solution was placed at 10 mbar And temperature &lt; 2 5 T: concentrated to a volume of about 12 liters at this time. At this point, the product has been removed from the solution Shen Dian, but when the mixture is heated to 50 ℃, it is dissolved into a solution. Analysis of a homogeneous whole shows a concentration of 10 The concentration is 341 g / l. The concentration is determined by HPLC: 25 cm DuPont Zorbax RXC8 column, 1.5 ml / min flow rate and detection at 210 nm, isotopic dissolution (98/2) CH3CN / 0, 1 ° / 0 water 仏1 &gt; 〇4 Retention time of 10: 2.5 minutes. Adding acetonitrile (39 liters) and water (2.4 liters) to obtain a transparent, light brown solutiona. iHNMR integrated CH3CN / 1-propanol ratio showed that the ratio of CH3CN / 1-propanol / H2O was 26/8 / 1.6. The concentration of the solution was 72.2 g / L. Within 30 minutes, at 20 ° Under C, add (S)-1 0-camphorsulfonic acid in four times. The temperature rises to 40 after CSA is added. (:. After a few minutes, a thick white precipitate is formed. The white slurry is heated to 7 6 ° C to dissolve all solids, and then allowed the light brown solution to cool to 2 1 ° C within 8 hours. The product precipitated at 6 2 t. Not at 2 1. (: the product will be filtered under aging, and -34-this paper is applicable China National Standard (CNS) A4 specification (210X297 mm) 4? Li patent application front page (December 88) A7 B7 j ^ Wn__ λ a. Description of the invention (5 liters of CH3CN / 1-propanol / h2〇 ratio of 26/8/1 1.6 solvent mixture was used to wash the filter cake. The product was placed in a vacuum oven and dried under N 2 at 35 ° C to obtain 5.6 kg (39%) of 1 1 ,for White crystalline solid, melting point 28 8 — 290 t (with decomposition) [a;] D25 = u.9. (C = 0.37, H2O). &quot; CNMR (75 MHz, D2〇, ppm) 222.0, 1 64.0, 59.3, 54.9, 5 3.3, 49.0, 48.1, 43.6, 43.5, 43.1, 40.6, 40.4, 28.5, 27.2, 25.4, 19_9, 19.8. According to the following enantio-HPLC analysis: 1 1 aliquots (33 mg) were suspended in 4 ml of EtOH and 1 ml was added to Et3N. The ee of the product was 95%. Boc 2 0 (11 mg) was added and the mixture was aged for 1 hour. The solvent was completely removed in vacuo, and the residue was dissolved in about 1 ml of EtOAc, and then passed through a pasteur pipet equipped with Si02. EtOAc was used as the eluent. . The evaporated product portion was re-dissolved in hexane at about 1.00 mg / 1 ml. Enantiomers were separated on a Daicel Chiracell AS column using a Tiger / IPA (97 ·· 3) solvent system at a flow rate of 1 ml / min and detected at 22 8 nm. Residence time; S enantiomer = 7.4 points, R = 9.7 points. Example 9. Preparation of (S) -2-Third-butylcarboxamidine-4-Third-butoxycarbonyl- from -Salt 1 1-(Please read the precautions on the back of Jing before filling this page) Ministry of Economy Central Procurement Bureau staff consumer cooperatives printed hydrogen p pig

* 2 (+)-CSA (b〇c) 2〇 CONHi-Bu 11

Boc NN ..... N CONHt-Bu H 4 35-This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) for profit application case Weiyongzheng ## 正 页 (December 88) A7 B7 V. Description of Invention (33

Kc: 5.54 kg (8.53 moles) printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs 8.6 kg (8.5 3 moles) 5.95 liters (42.6 moles) 55 liters 2 liters Next, add three raw materials at 25 ° C

(S) .2 · Di-tri-butylamine-hexahydro p ratio Gengshuang (S)-(+)-CSA salt 1 1,95% ee Tri-third-butyl hydrogen carbonate E13 N

EtOH Punctilous 200 ^

EtO Ac EtOH was added to the (S) -CSA salt 11 and ethylamine in a 100 liter 3-necked flask under N2. The solid dissolved immediately when Et3N was added. B 0 c 2 0 was dissolved in E t 0 A c and added to the addition funnel. The E10 A c solution of B 0 c 2 0 was added at a rate capable of maintaining the temperature below 25 ° C. Adding work takes 3 hours. After the addition of the B 0 c20 solution was complete, the reaction mixture was aged for 1 hour. The reaction can be detected by PLC: 25 cm DuPont Zorbax RXC8 column, 1 ml / min flow rate and detected at 2 28 nm, allelic dissociation (5 0/5 0) CHs CN / 0.1M KH2P〇4 to NaOH was adjusted to pH = 6.8. Dwell time of 4 = 7.2 minutes. Enantiomeric analysis was performed using the same system as the previous steps. The reaction can also be detected by T L C with 100% E t Ο A c as the solvent. (R r = 0.7). It is then concentrated in a batch concentrator under vacuum at 10 mbar to about 10 liters at an internal temperature &lt; 20 ° C. The solvent conversion was completed by slowly putting 20 liters of E t Ο A c and the solution was concentrated to about 10 liters. The reaction mixture was washed with 60 liters of E tO A c into the extractor. The organic phase was washed with 16 liters of a 5% Na2C03 aqueous solution, 2 X 100 liters of Di water, and 2 X 6 liters of a saturated sodium chloride aqueous solution. The combined aqueous washing solution is back-extracted with 20 liters of EtO Ac, while the organic phase is saturated with 2 X 3 liters of water and 2 X 4 water -36. This paper size applies to national standards (CNS &gt; A4 specifications (2 丨 0X297 mm) ) (Please read the precautions on the back before filling out this page), install -------- order ------ 415948 A 7 B7 V. Description of the invention (34) '' Gasification water drop liquid washing strips. Merge The E10 A c extract was concentrated to about 8 liters at 100 mbar in an 100 liter batch concentrator under 100 mbar air, by slowly putting in about 20 liters of cyclohexane. The solvent was converted to cyclohexane and concentrated to about 8 liters. To this slurry was added 5 liters of cyclohexane and 280 ml of EtOAc and the mixture was heated to reflux. At this point everything was dissolved into a solution. Seed crystals (10 g) were added to C. The slurry was cooled to 2 ° C within 4 hours, and after aging at 2 C for 1 hour, the product was separated by filtration. The filter cake was washed with 1 s of cyclohexane. It was dried at 35 ° C in a smelting furnace with a degassing oven to obtain 1.87 kg [77%, &gt; 99.9 area% (HPLC), the R-isomer is below the detection level). The 4 'is Hazel powder = [(^]; [) 25 = 22.0. (C = b.20, MeOH) 'Melting point 107eC; 13CNMR (75 MHz, CDC13, ppm) 170.1, 154.5, 79.8, 58.7, 50.6, 46.6, 43.6, 43.4, 28.6, 28.3 〇 Although the foregoing description illustrates the principles of the present invention and provides examples for illustrative purposes, it should be understood that the practice of the present invention covers all common variations of the procedures and principles described herein. And increase: These are all within the scope of the following patent application parks of the present invention. (Please read the notes on the back and then “I”). Packing. Standards of the Ministry of Economic Affairs, Central Standardization Bureau, Off-line Consumer Cooperatives, Printed Paper Scale Applicable to China National Standard _ (CNS) A4 specification (2! 0χ297 mm)

Claims (1)

Revision of Chinese Patent Application Range (88 丨 丨 February 88) Scope of Patent Application 1. A method for synthesizing epoxides with the following chemical formulas Including the following steps: a) Provide a certain amount of allyl allyl with the following structural formula (Please read the precautions on the back first and fill out this Vs.) -: ¾ Printed by the Male Workers Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs and made into an aqueous mixture with Nanyan 'and water-miscible co-solvents between 0.2 and 2.0 equivalents; b) at temperatures between 0 ° C and 3 5 ° Under C, the mixture is subjected to a current density night between 〇ΙΑ / cm2 and 0.5A / cm2; c) to obtain the desired epoxide "2. A method for synthesizing a functional enzyme with the following chemical formula: This paper size applies to Chinese standards (CNS &gt; A4 size (210 X 297 mm)) Known application Chinese patent application scope amendment (88 丨 February 88) Scope of Patent Application 1. A method for synthesizing epoxides with the following chemical formulas Including the following steps: a) Provide a certain amount of allyl allyl with the following structural formula (Please read the precautions on the back first and fill out this Vs.) -: ¾ Printed by the Male Workers Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs and made into an aqueous mixture with Nanyan 'and water-miscible co-solvents between 0.2 and 2.0 equivalents; b) at temperatures between 0 ° C and 3 5 ° Under C, the mixture is subjected to a current density night between 〇ΙΑ / cm2 and 0.5A / cm2; c) to obtain the desired epoxide "2. A method for synthesizing a functional enzyme with the following chemical formula: This paper size applies to Chinese standards (CNS &gt; A4 size (210 X 297 mm). Printed by the Bayer Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs «. 415946 A8 BS C8 ______ D8 6. Where the patent is applied, where x is the tooth base; Contains the following steps: a) Provide a certain amount of allyl propionate with the following structural formula And an aqueous mixture with a salt and a water immiscible solvent between 0.2 and 2.0 equivalents; b) at a temperature between 0 t and 35. (:, The compound is subjected to a current density between 0.001 A / cm2 and 0,5 A / cm2; c) to obtain the desired functional alcohol. 3. The method according to item 2 of the scope of patent application, wherein the halogeno group other than iodo group is bromo group. 4. The method according to any one of items 1 to 3 of the scope of patent application, wherein the salt system is selected from the group consisting of Nal, NaBr, KI * KBr, Et4NI, and Et4NBr. The method according to the item, wherein the water-miscible co-solvent is selected from the group consisting of THF, acetonitrile, DMF, and NMP (N-methylpyrrolidone) and mixtures thereof. 6. The method according to item 2 or 3 of the scope of the patent application, wherein the water-immiscible solvent is from ethyl acetate, isopropyl acetate, related esters, methylbenzene, and methylene. ; CNS) Α &lt; 4 specifications (210X297 mm) installed --------------- ί line (please read the precautions on the back before filling this page) 415946 Αβ Β8 C8 D8 Selected from the group consisting of gas and related denting solvents. 7According to the material of t] — β: The electrification process is performed in the unshunted battery, and the temperature range is between two: ") c under mMG.iA / em2-the period is between 丨 and 10 hours Time to complete the reaction. S 'A method of synthesizing an epoxide with the following chemical formula Including the following steps: a) Provide an equivalent of allyl acetal with the following structural formula (Please read the precautions on the back before filling this page) II. Order Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Ph Aqueous suspensions were prepared with B-water / Kun compound containing between 0.2 equivalents and 2.5 equivalents of NaBr; b) the suspension was subjected to current density in an undivided battery at a temperature of 20 ° C 0 · 1 A / c m2 lasts from 1 hour to 10 hours; the standard of this paper is applicable to China's national standard {CNS) A4 specification (210 χ 297 male thin) 415948 μ C8 D8 6. The scope of patent application c) Oxide. 9. A method for synthesizing a halogenated alcohol having the following chemical formula Wherein X is chloro or bromo; comprises the following steps: a) providing an equivalent of allyl acetal having the following structural formula (Notes on the back of Shi Xianmin read this page before filling out this page) -5 The policy of employee consumer cooperatives of the Central Government Bureau of the Ministry of Economic Affairs and the content of ethyl acetate or propyl acetate between 0,2 equivalents and 碣 5 equivalents Nal or NaBr make a two-phase system; b) make the two-phase system in an unshunt battery at a temperature of 20 ° C * withstand current density 0.1 A / cm2 for 1 hour to 10 hours; c) get what you want Tooth alcohol. -4-This paper is fully compliant with Chinese National Standard (CNS) A4 # See grid (210X297 mm)