TWI331605B - A process for the preparation of racemic citalopram diol and/or s- or r-citalopram diols and the use of such diols for the preparation of racemic citalopram, r-citalopram and/or s-citalopram - Google Patents

Description

1331605 A solution of s-diol in acetonitrile (5 liters of about 5 〇 55% w/w, S:R ratio 95.72: 4·28) was stirred and cooled to _14 at room temperature. C. At 2. An almost racemic diol (s:r ratio of about 6 Torr: 40) was added dropwise at C temperature to inoculate the mixture. After a force of 16 +, the mixture was transitioned and the filter cake was dried. The analytical filter cake showed an s : R ratio of 57 97 42.03. The analysis of the mother liquor showed an s : R ratio of % 〇 65 : ^ 5 . Example 3 A solution of s-diol in acetonitrile (5 〇 0 ml of about 5 〇 55% w/w φ , 3: 尺 ratio) by precipitating a racemic diol free base to purify s• diol 95.72: 4.28) 1 at room temperature. (:/hour rate, stir and cool to -10 ° C. Add almost racemic didecyl alcohol (S: R ratio about 6 〇: 4 〇) at a temperature of 5. C to inoculate the mixture. After 4 hours, the mixture was filtered and the filter cake was dried. The analysis cake showed an S:R ratio of 59.19: 4 〇 81. The analysis of the mother liquor showed a ratio of s:R of 98.52: 1,48. Example 4 Purification of s-diol by precipitation of a racemic glycol to a hydrochloride salt. General method: Mixture of R- and S-diols (as defined in the table below) (j g Dissolved in toluene (10 ml). Add aqueous hydrochloric acid (1 〇 equivalent, as defined in the table below), and add solid sodium sulphate (sufficient amount to make NaCl concentration in water is about 1 or 2 M; see table below. The mixture was stirred overnight and filtered. The residue was dried to give racemic diol salt crystals containing some of the S-diol salt. Water-soluble 29 1331605 liquid alkalized the mother liquor to pH > 9, and separated from the field, and the knife leaves the layer. The layer is watered with toluene. The extract is again extracted, and the combined formazan & + stroke liquid is dehydrated with magnesium sulfate and evaporated under reduced pressure to obtain the main _ (four) main S-monosterol of a small amount of R-diol. See the table The recovery rate of the substance is almost the same as that of the whole person. 卞. 卞马王$, has the expected weight distribution between individual samples. 1^1 The concentration of the HCl compound HCl solution before the rescue (M ) NaCl aqueous solution concentration (M) Shen; children's moving material (mixture of R- and S*·diol) After the rescue, separation and evaporation, it is an oil (rich in S-mirror isotopes Ί S%) R% S% R% S% 03⁄4 82.3 17.7 1.0 1.0 58.4 41.6 99.4 IV/0 0 β 82.3 17.7 2.0 1.0 49.7 50.3 97.7 2 3 82.3 17.7 1.0 2.0 81.3 "18.7 86.2 13.8 82.3 17.7 2.0 2.0 60.1 39.9 99.7 0.3 Example 5 Purification of S-diol by precipitation of the racemic glycol to p-toluenesulfonate, decanesulfonate or acetate General method: β A mixture of R- and S-diols (as below) (defined in the table) (ι) is dissolved in toluene or ether (1 〇 ml; as described in the table below). Aqueous NaCl solution (丨μ, 3 ml). Add pure acid (as defined in the table below) in liquid form. Stir the mixture overnight and filter or decante to dry the residue to give an oil. Or a solid. The mother liquor is alkalized to pH > 9, using an aqueous ammonia solution, and a layer of ruthenium or diethyl ether is isolated. The aqueous layer was extracted once more with benzene or diethyl ether. The combined organic extracts were taken from <RTI ID=0.0>> Table loses the list of details. The recovery of the substance is almost the full amount of M a ^ ^ V with the expected reset distribution between individual samples.战战之俞------ isophthalate mixture solvent acid (equivalent) stimulator (R- and mixture) 殿之猞03⁄4 DW: diol alkalization, separation and evaporation after oily (Enriched S-mirroromer) 〇/〇82.3 two 17.7 Toluene MsOH (1) S% 64. Plant 35 fi S% R% 94.3 5.7 82.3 17.7 Toluene MsOH (2) 48.2 Cl A 82.3 17.7 Ethyl ether MsOH ( 1) 62.9 i) 1.8 37 1 90.0 10.0 82.3 17.7 Ethyl ether MsOH (2) 55.1 44.9 91.0 89 3 9.0 82.3 17.7 Ac Ac AcOH (1) AcOH (2) 71.3 65. 9 — 34.1 96.2 94 8 10. 7 3.8— 82.3 17.7 曱 C C 〇 82.3 17.7 Ethyl ether AcOH (1) 65.0 35.0 91 6 p A 82.3 | 17.7 Ethyl ether AcOH (2) 65.7 87.2 〇. 4 12.8 Example 6 Purification by precipitation of the racemic diol salt without water General procedure for s_diols: A mixture of R- and S-diols (as defined in the table below) is dissolved in toluene or diethyl ether (10 ml; as described in the table below) . The pure acid is added as a solid (as defined in the table below). The mixture was stirred overnight and filtered or decanted. The residue is dried to give an oil or a solid. Water was added to the mother liquor _, and the mother liquor was alkalized to pH > 9, using an aqueous ammonia solution, and a toluene layer or a diethyl ether layer was separated. The aqueous layer is re-extracted once with terpene or diethyl ether. The combined organic extracts are dehydrated with magnesium sulfate and evaporated under reduced pressure of 31 丄丄ου:), which is mainly a solid or an oil. See the details listed in the table. The recovery of the substance is almost full and has the expected weight distribution between individual samples. __ Precipitation - pre-solvent _____ after precipitation, fart acid (equivalent) Precipitate (mixture of R- and s-diol) After oiling, separation and evaporation, it is oily (rich in S- Mirroring different S% R% S% R% S% m J_2.3 17.7 A Stupid TsOH (0.4) 54.9 45.1 90.9 8 1 —82.j 17.7 _Ethyl ether TsOH (0.4) 57.4 42.6 98.1 7 9 82.3 17.7 Benzene (C02H) ) 2 (0.2) 78.4 21.6 93 7 Like .3 17.7 Benzene _) 2 (0.4) 72.1 27.8 99.97 0 03 82.3 17.7 Benzene (C02H) 2 (1) 82.2 17.8 99.6 0 4 82.3 17.7 Ether (C02H) 2 ( 0.2) 58.0 42.0 97.7 2 3 _82.3 17.7 Ethyl ether (_2 (0.4) 55.4 44.6 98.4 16 82.3 17.7 diethyl ether _) 2 a) 72.0 28.0 99.5 0.5 Example 7 Precipitation binary via two kinds of solvents without water Alkoxide to purify S-diols. General method: Mix a mixture of R- and S-diols (as defined in the table below) (g) in a solvent (10 ml; as shown in the table below) In the above, β is added as a solid acid in a solid form (as defined in the table below). The mixture was stirred overnight and filtered or decanted as it formed a precipitate. In the case where a precipitate has been formed, the residue is dried to obtain an oil or a solid. The mother liquor was evaporated' and the residue was taken up in a mixture of diethyl ether and water. The mother liquor was assayed to pH > 9 with aqueous ammonia solution at 32 ^ 31605 and B (tetra) was isolated. The aqueous layer was re-extracted by means of the test, and the combined liquids were extracted by dehydration of sulfuric acid and reduced under reduced pressure to obtain a solid or oily substance. See the details listed in the table. The recovery rate of the material is a few hands. The Millennium Bureau has the expected weight distribution between individual samples. 98.2 1.8 98.5 1.5 99.6 0.4 ~~

Example 8 Desalination of a glycol oxalate via precipitation to purify s_ _ _ s ^ · General method: as defined in the table) (1 aqueous solution (1 Μ, 3 mM R- and S-diol) The mixture (eg gram below) was dissolved in toluene (10 mL) "NaC1 33 Ϊ 331,605 liters) and pure oxalic acid (as defined in the table below) was added as a solid. The mixture was stirred overnight and formed The precipitate is subjected to hydrazine or decantation. In the case where a precipitate has formed, the residue is dried to obtain an oil or a solid. The mother liquor is alkalized to pH > The layer is re-extracted once with toluene, and the combined toluene extract is dehydrated with magnesium sulfate and evaporated under reduced pressure to give a crude solid or an oil. See the table for details. For the full amount, there is expected weight distribution between individual samples. Precipitation-pre-----precipitate mixture of oxalic acid (equivalent) precipitate (mixture of R- and S-diol) Oily mirroring after verification, separation and evaporation S) R% S% R% S% R% 82.3 17.7 0.2 51.8 48.2 98.5 15 82.3 17.7 0.4 62.6 37.4 99.8 0 2 82.3 17.7 1.0 58.6 41.4 97.0 3.0 82.3 17.7 2.0 56.7 43.3 92.7 7.3 Example 9 by precipitation in water General method for the purification of s-diols by racemic diols: a mixture of R- and S-dioxanol (as defined in the table below) with an aqueous solution of HCl (1 equivalent; see table Indicate the concentration). The mixture was stirred overnight and a sufficient amount of NaCl (solid form) was added to give a NaC1 concentration! Hey. According to the mixture, a solid is obtained. Water and a puzzle were added to the mother liquor, and an aqueous ammonia solution was used to test to ρΗ > 9, and the test layer was separated. The aqueous layer was re-extracted once with diethyl ether. The combined ether extracts were either sulphuric acid 34 1331605 or an oil. Refer to the table, with the expected details of the main solids in the dehydration and evaporation under reduced pressure. The recovery of the substance is almost the weight distribution between all individual samples. Before Precipitation---------- HC1 Concentration (M) ——— 彳 井 俯 俯 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (rich in S-mirror isomer) S% R% S% R% S% D叱82.3 17.7 1 59.4 40.6 99.2 IVD π R 82.3 17.7 2 63.7 36.3 99.3 U. 〇0.7 " :--1 Example 1 〇 Left by purifying the s-diol hydrochloride in water to purify the diol. General procedure: Mixture of R- and S-diol hydrochloride (17 7: 82 3; 5.5 g) With aqueous solution of NaC1 0 M' 12 ml) (d). The mixture was sifted overnight and filtered to obtain a solid stomach. Water and diethyl ether were added to the mother liquor, and alkalized to pH > 9, using an aqueous ammonia solution, and the test layer was separated. The layer was re-extracted once with acetonitrile, and the combined ether extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a crude solid or oil. The residue obtained by filtration contained a ratio of 1.0: 99.0 @ R•diol and s glycol. The product obtained after the filtrate was collected and processed contained R diol and s- sterol in a ratio of 38 8:61 2 . The recovery of the substance is almost full and has the expected weight distribution between individual samples. 35 July V曰修(吏) is replacing page Announcement Buben Patent description of the invention (When the format, order and bold text of this manual are used, please do not change it arbitrarily, please do not fill in the ※ part) ※Application Sfe:

※Application date: p 1 PC classification: cc;?·^ 9 壹, invention name: (Chinese / English) 44, K

Preparation, cital 〇pram diol and/or 8_ or R_ cypland binary and these diols for the preparation of racemate, R-Sipran and/or S-Sipland A process for the preparation of racemic citalopram diol and/or S- or R-citalopram diols and the use of such diols for the preparation of racemic citalopram, R-citalopram and/or S-citalopram 贰, applicant: (total 1 person) Name or name: (Chinese / English)

Η·Lundbeck Company / H. LUNDBECKA/S Representative: (Chinese / English) (signature)

Lars Kejlang Calder / KJERRUMGAARD, LARS residence or establishment address: (Chinese / English)

Denmark ' DK-2500 Fabi - Copenhagen, Otili Yavi 9 9 Ottiliavej 9, DK-2500 Valby-Copenhagen, DENMARK

Nationality: (Chinese / English) Denmark / DENMARK Participation, inventor: (4 in total) i Name: (Chinese / English)

Hans Peterson / PETERSEN, HANS Residence Address: (Chinese / English) Danish DK-2720 Fanlos City, Gurdag Street u Guldagervej 11, DK-2720 Vanl0se, Denmark Nationality: (Chinese / English) Denmark / Denmark 1331605 Di, invention description: [Technical field to which the invention pertains] The present invention relates to a method for preparing a citalopram diol and an S- or R celand-alcohol, including a compound R- and a Primal diol (R- and S_4-[4-(didecylamino)-bu (4,-fluorophenyl; hydroxybutyl]3-(indolyl)-benzonitrile) The separation of the rotatory mixture into a fraction of a racemic cedar diol and a s-diol or R-diol-rich portion of the invention is also related to the separation of the cedar diol from the 4 To form a corresponding elimination; 5 sputum sipram and / or S _ or R - siplan in order to include the use in a pharmaceutical composition. [Prior Art] cedar is a well-known antidepressant drug, which is still in the market Upmarketing for many years and has the following structure··

The cisplatin can be ring-closed by 4-[M-diamine-amino)succinyl (4,- phenylphenyl) hydrazino][3](rutyl)benzonitrile as described in U.S. Patent No. 4,650,884. Prepared as. The product cedar is a racemic mixture of the R- and S di-isomers. In addition, 'escitalopram' is an anti-depressant with s_mirror isomer (Sexiective serotonin reuptake inhibitor (SSRI) type). S-4-[4-(dimethylamino)-1-(4,-fluorophenylhydroxybutyl]_3_(hydroxyf-yl)-benzonitrile (S) can be obtained as described in EP B1 347 066 - diol) is prepared by ring closure in a retained configuration. The amount of R- cypran relative to s- cymidine in the product ethidium must be less than 3%. Furthermore, a method is described in WO 03000672 A process for the preparation of a mixture of R- and S-sirram containing more than 5 % s-mirrion isomers from a mixture of R- and S-diols containing more than 5 % r_diol.

It will be apparent from the above that it is desirable to have the racemic cisplatin and ethiprom products of the above-described imagery isomer purity for the preparation of pharmaceutical compositions and the eciram product can be via RS_diol and R_two. It is prepared by ring closure of alcohol and/or 3-diol. As a result, a method of preparing a racemic diol having a corresponding mirror image purity and an S-diol product is required. The methods used to prepare and alcoholize the R- or S-diol product are all desirable. Such methods include, for example, mirror-selective synthesis as described in Ep 〇 347 〇 66, conventional resolution (resGluti() n) and chromatographic separation as in

As described in W〇〇3006449. Depending on the particular method and conditions employed, it may be necessary to improve the image-isolated purity of the s-diol product prior to meeting the above requirements for the 纟S-diol product. It is surprising that it has been found that by using the process of the invention, expensive but "useless miscellaneous [diol-alcohol products can be readily converted to s-diols, which all comply with the above-mentioned image isomer purity) Requirements. Furthermore, by using the method of the present invention, it is possible to easily convert the product of the alcohol containing the s-diol into two valuable substances, the racemic diol and the R diol, by using the method of the present invention. They all meet the above requirements for image isomer purity. More particularly, the present invention proposes an initial non-racemic S_M4_(diguanylamino) small (4, _ = yl) small butyl butyl group having more than 5% by weight of the mirror image isomers. · (10) fluorenyl) Benzonitrile mixture is separated into a = s-diol "R. diol part and a part comprising rs_ diol" where R-diol: S- The ratio of glycol is equal to i: [or closer to i: i than in the starting R- and S-diol mixture. The present invention is important and very useful, especially because it provides a convenient & efficient method for converting R- and S-diol mixtures that do not meet the above requirements for image isomer purity to two A valuable product that meets the above requirements for mirror image purity, rs•diol and S-diol (or R-diol). In another aspect, the present invention provides a convenient, inexpensive, and efficient method for making an intermediate product for use in the manufacture of celand and escitrin. When using the invention, the method of manufacturing ceplan and escitram that meets the requirements of individual market approvals becomes more reasonable and more economical in terms of the simplicity of the method and the utility of the pharmacy and resources. SUMMARY OF THE INVENTION Brief Description of the Invention Accordingly, the present invention relates to a process for preparing a racemic glycol free base and/or an acid addition salt and/or an R- or S-diol free base and/or an acid addition salt. Method - 10 1331605 'Including the separation of the non-racemic mixture of the starting R and s-diethanol free base and/or the acid addition salt containing more than 50% of the mirror image isomers into a field 3 S unitary a portion of an alcohol or a mono-alcohol free base and/or an acid addition salt and a portion comprising an RS-diol free base and/or an acid addition salt, wherein the R-diol: s-binary The ratio of alcohol is equal to i: i or closer to 1: 1 than in the mixture of starting R and 8_diol, where i) from the starting R- and S-diol free base and/or A solution of a non-racemic mixture of acid addition salts precipitates an RS_diol free base and/or an acid addition salt; or a "free start of R- and S-monohydric alcohol and/or an acid addition" A solution of the salt non-racemic mixture in a solvent dissolves the R- or s-diol free base and/or acid addition salt in the solvent, leaving the RS-diol free base and/or acid Residue of addition salt; u) from After the solution phase separates the formed residue/precipitate; iia) if the residue/precipitate is crystalline, it is recrystallized one or more times as needed to form a racemic glycol; iib) if the remainder When the substance/precipitate is not crystalline, step 1) and step U) are repeated as needed until a crystalline residue/precipitate is obtained and the crystalline form residue/precipitate (4) needs to be recrystallized one or more times to form Racemic Glycol; Π1) If necessary, the final solution phase is further purified and the 3 -glycol or saponin-diol free base and/or acid addition salt iv is removed from the final solution phase knife) The obtained diethanol free base is converted into its acid addition salt as needed [9 1331605. The obtained glycolic acid addition salt is converted into another acid addition salt as needed or the obtained glycolic acid addition salt is obtained. If necessary, the resulting RS-diol free base and/or acid addition salt can be produced - although containing S- or R-diol free base and / or acid addition The final solution phase of either salt. The remaining R- or S-diol free base and/or acid addition salt can then be separated from the final solution phase as described below. According to a particular embodiment, the invention relates to a process for the preparation of a red-and-sterol free test and/or an acid addition salt using the above process. According to another specific embodiment, the present invention relates to a process for the preparation of an S-diol (or R-diol) free base and/or an acid addition salt using the above-described method. According to yet another specific embodiment, The present invention relates to a prepared / spirulinol free base and / or acid addition salt and / or s - glycol (or R - bis = alcohol) free base and / or acid addition salt is used below The process employs the use of racemic cedar and/or S- cypress (or R- cypland) free base and/or acid addition salts.

DETAILED DESCRIPTION OF THE INVENTION As used in this document at any time, the terms "Hong diol" and S- cypress diol, mean s_4_[4_(dimethylamino) small (4, qi Phenyl octa-l-hydroxybutyl]-3-(hydroxymethyl)·benzonitrile. As used in this document at any time, the term "R_diol, and" R. siplan II "Polyol" means R_4_[4•(diamidoamine) small (4,fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-stanocarbonitrile. At any time in this document When used, the term "RS_binase 12 丄丄 OU:)" means a mixture of R- and ς 〇^ ΛΑ Λ c S• diol such as R- and S-diethanol 0.5 : or 0·9 . ll or 0.95 : 1·〇5 or 0.98 : 1.02 or 0.99 : L01 deduction and preferably a 1:1 mixture of R· and S-diol. : At any time in this document When used, the term "diol mirror image isomer" and _ - , _ 4^ - sterol isomer, meaning either s- or R-dialdehyde. Whenever used, the term "racemic diol" is a 1: 1 mixture of R and S - diols.The term "non-racemic diol σ" refers to a mixture of R- and S-diols in ratios other than 1:1.

As used at any time in this document, the term "Sipran mirrored eight-structure and sipram isomer" means either s- or R-Cypress. At any time in this document. When used, the term "racemic cymidine" refers to a 1:1 mixture of R- and s_ sipland. The term "non-racemic sipland" is intended to mean a mixture of R- and s_ cypress in a ratio other than 1:1. As used in this specification, the term, precipitation, means from the beginning A solution of a non-racemic mixture of monohydric alcohols in a solvent forms a sputum form, an amorphous solid or an oil or a mixture thereof.

In the description, the precipitate may be an oil, an amorphous solid or a crystal or a mixture thereof. From: From the description of this part: the user's terminology "residue" is referred to as . _ or S • The non-racemic mixture of the diol will be the residue remaining after the R· or S-di-guang~ mixture. The remaining crystalline solid or oil or a mixture thereof. 4th day, non-precipitate or residue as defined by the user's terminology/precipitation surface as used herein.

OVD The user, term, mother liquor, (m〇t from the sediment 峪 峪 灿 〖 〖quorj u 牙 夕 夕 夕 夕 夕 夕 夕 夕 夕 夕 夕 夕 夕 夕 夕 夕 夕"From the choice of R- or S-diols | · raw / gluten-dissolved organic, the first aqueous phase from the starting R- or s-diol does not dissolve R- or s- two The phase obtained from the diol. "The user, term, and final solution phase, as used herein, refers to a mother liquor or an organic and/or aqueous phase obtained by selective dissolution of a s-diol such as s. The above-mentioned methods for preparing citrin free test and/or acid addition and/or ethidium free base and/or acid addition salt may result in not being accepted by the medicinal use. # R•和s西Mixan free test and / or acid addition salt mixture. According to the present invention, a surprisingly efficient preparation for the preparation of racemic cymidine free and / or acid addition salts with R- or S · West has been found Method for freely detecting and/or acid addition salt of racemic diol and R- or S-dioxa alcohol free base and/or acid addition salt Such novel methods include the separation of the non-racemic mixture of the starting han and 8 diol free bases and/or acid addition salts into a racemic diol free base and/or acid addition salt. And a part comprising a ruler or s_: a free alcohol and/or an acid addition salt. The part of the racemic diol free test and/or acid addition salt is precipitated from a solvent to an oil , amorphous solid or crystalline form or a mixture thereof, and the ruler or s_diol free base and/or acid addition salt is separated from the final solution. Then, the corresponding racemic The steroid free base and/or the acid addition salt and the R_ or diol free base and/or acid addition salt form a racemic cisplatin free base and/or an acid addition salt and R_ or via a ring closure s _ West: 1331605 Planan free base and / or acid addition salt. According to another aspect of the invention, the non-racemic nature of the initial HCl and s diol free test and / or acid addition salt The mixture is separated from alcohol or R-glycol free base and/or acid addition salt _ J. 丨 injury and a portion including RS-diol free test and/or acid addition salt, 1

''A R-glycol: S-glycol ratio is equal to 1: i or closer to 1:1 than in the starting R ^ ύ - X alcohol mixture, including the starting Han_ and _ ^ - sterol free test and / or non-racemic mixture of acid addition salts 盥, _ _,, mixture mixture and make R- or S- diol free test and / or acid addition salt priority Dissolving, hydrazine/recombination in the solvent, followed by separation of the organic and/or aqueous phase from the R- or S-monohydric alcohol free test and/or the selective dissolution of the acid force π into a Dissolved RS -; diarrhea liver J Kb - lysate free base and / or acid addition salt and from the solvent to isolate R 戋 s _ 4 sterol free base and / or acid addition salt. ☆ The agent used in this embodiment according to the present invention may be any solvent which promotes the free detection of R- or S-sterol and/or the preferential dissolution of the acid addition salt to leave the T RS-diol free as a residue. a mixture of bases and/or acid addition salts, wherein the ratio of R_diol:s-diol is equal to 1:1 or closer than in the mixture of R- and S-diols i : i. The non-racemic mixture of the starting ruthenium and S-diol free base and/or acid addition salt used in the process of the invention may be in the form of an oil, an amorphous solid or a crystalline form; or mixture. The residue/precipitate formed in step 1) may be in the form of an oil, an amorphous solid or a crystalline form or a mixture thereof. The remainder/precipitate formed in step i) is preferably in crystalline form. 15 1331605 According to one embodiment of the invention, the non-racemic mixture of the starting R_ and S-70 alcohol free bases and/or acid addition salts used in the process of the invention contains more than 50% of the S-diol' or More preferably, more than 7 % s diol or more preferably more than 90% S diol. According to another embodiment of the invention, the non-racemic mixture of the starting R- and S-diol free base and/or acid addition salt used in the process of the invention contains less than 99.9% S-diol, For example less than 99.5. /. S-diol, or less than 99 ° /. S-diol, or less than 98 ° /. S-diol. Accordingly, the non-racemic mixture of the starting R- and S-diol free base and/or acid addition salt may contain 50%-98% S-diol, or 50%_99❶/〇S. a glycol, or 50% to 99.5% S-diol, or 50% to 99.9% S-diol, or 70%-98. /. S-diol, or 70%_99% S-diol' or 70%-99.5% S-diol, or 70%-99.9% S-diol' or 90% - 98% S-diol, or 90% - 99% S-diol, or 90 ° /. - 99.5% of 1 glycol, or 90% - 99.9% of 8-diol. According to another embodiment of the invention, the non-racemic mixture of the starting R- and S-diol free base and/or acid addition salt used in the process of the invention contains more than 50% R-diol' or More preferably, more than 7 % of the metric diol or diol is more than 90. /. R-diol. According to still another embodiment of the present invention, the non-racemic mixture of the starting R- and S-diol free base and/or acid addition salt used in the process of the invention contains less than 99.9% R-diol For example, less than 99.5% of R-diols, or less than 99% of R-diols or less than 98% of R-diols. Accordingly, the starting R- and S-diol free base and/or acid addition salt [16 1331605 non-racemic mixture may contain 50%_98% R_diol, or 50%-99% · R-diol, or 5〇%-99.5% R-diol, or 50%-99.9%. R-diol, or 70%_98% R-diol, or 70 %-99% R-diol, or 70%-99.5% R-diol, or 70%-99.9% R-diol' or 90%_98% R-diol, or 90%-99% R-glycol, or 90〇/. -99.5% R-diol, or 90%-99.9% R-diol. This process can be repeated until a racemic mixture of r- and S-diol is obtained and/or until a desired image isomer purity of the ruler or §-diol is obtained. According to one embodiment of the invention, the residue/precipitate RS-diol is in the form of a free base and/or an acid addition salt; and the final solution phase of the R_ or S-diol is independently Free base and / or acid addition salt form. Accordingly, when the RS_diol contained in the residue/precipitate is in the form of a free base, then the ruler or s_diol included in the final solution phase may be a free base, 酉文加In the form of a salt or a mixture of free test and acid addition salts. Further, when the Rs_diol included in the residue/precipitate is in the form of an acid addition salt, the ruler or s_diol included in the final solution phase may be a free base, A mixture of a sulfonium salt or a free test and an acid addition salt. Finally, when the RS_diol contained in the residue/precipitate is a free base and a /3⁄4 δ of the acid addition salt, the I or glycol included in the solution phase can be free. a base, an acid addition salt or a mixture of a free base and an acid addition salt. The starting R- and S-diol non-racemic mixture used in the process of the invention may be a free base, a salt or a free base and a salt. The form of the mixture. [00] 17 !3316 〇 5 Further, the obtained diol _ free base can be converted into its acid addition salt or added to the obtained glycol acid using a method known to those skilled in the art. Conversion to other acid addition salts or addition of the resulting glycolic acid as needed - is converted to the corresponding free test. The preparation of the RS-glycol free base can be carried out by obtaining a non-racemic mixture of the anti- and s-diol free base and/or the acid addition salt or by adding the R and s-diol free base and/or acid. The salt-forming non-racemic mixture is dissolved in a suitable solvent 'heated as needed, and then the solution is allowed to cool, or via cooling to below ambient temperature. The precipitate is then separated from the mother liquor, preferably by filtration or decanting. The residue of the RS-glycol free base can be treated with a S-glycol free base in a solvent via a non-racemic mixture of starting and/or acid addition salts from the starting and/or binary / or acid addition salt is selectively dissolved in the solvent to form, and then the residue is separated from the organic and / or aqueous phase obtained by selective dissolution of the ruler or s_diol. If the residue/precipitate is crystalline, the crystal may be 炙 Λ * ττ, , , , as needed.自由 Free from the elimination == glycol. Then, through the closed loop and the 疋----------------------------- The racemic acid I. From the base, it can be converted into its acid addition salt as needed, preferably hydrogen residue/precipitate as oil i) and step gentleman, β .... The crystal obtained may be formed one or more times from day to day to form a racemic glycol free base from the day after the reconstitution of the U. Racemic and can be formed from the racemic glycol free test via a ring closure reaction to form a second 18 1331605 to convert the racemic celand free base to its acid addition salt, preferably hydrobromic acid, as needed salt. The RS-diol free base prepared according to the present invention can be converted to its acid addition salt as needed. For the oil phase separated from the final solution phase, a conventional purification procedure can be applied as needed. The RS-diol free test prepared according to the present invention may contain a small amount of residual S-diol (or R-diol). It may therefore be necessary to repeat i) and step ii) (especially crystallization) one or more times for the RS_diol free base to obtain the oxime monol. The final solutions can be combined together and the diol mirror image isomers contained therein can be isolated as described below. Suitable solvents for obtaining the residue/precipitate comprising the RS-diol free base are non-polar solvents such as calcinations such as Gengyuan or hexane; aromatics such as toluene 'benzene and xylene; polar solvents such as acetonitrile Alcohols such as methanol and isopropanol or ketones such as methyl isobutyl ketone; or mixtures thereof. In a preferred embodiment, the RS diol free base in the step 丨) is preferably in crystalline form. Crystallization can be carried out freely by using a racemic crystalline crystalline diol as needed. Precipitation of the RS-dibasic acid addition salt can be carried out by obtaining a non-racemic mixture of the r- and s-diol free base or acid addition salt or by freely or adding a salt of the anti- and 8-diol The non-racemic mixture 〉 gluten is carried out in a suitable solvent, applying heat when needed, and adding an acid, for example, as a solid, a liquid, in the form of a solution s 1331605 or a gas. The acid used for the precipitation of the RS-dibasic acid addition salt is a mixture of a precipitable ruler and an s--mirrogram isomer and is enriched in R-. or S-di in the form of a free base or an acid addition salt. The acid of the mother liquor of the alcohol mirror image isomer. The acid used in the addition of RS-monohydric acid to the salt can be: • obtain a non-racemic mixture of the starting R- and S-diol free base and/or acid addition salt or will start r_ and 8 Adding a non-racemic mixture of a glycol free base or an acid addition salt after dissolution in a suitable solvent; and/or • at the beginning of the R- and S-diol free base and/or acid addition salt The non-disintegration mixture is present in the solvent during and/or prior to dissolution; and/or • is present in the starting R- and S-dittanol free base and/or acid during and/or prior to dissolution in the solvent Addition of the salt to the non-racemic mixture. The RS-diol free base residue may be a R- or S-diol in a solvent via a non-racemic mixture of starting r- and s-diol free base and/or acid addition salt The free base and/or acid addition salt is selectively dissolved in the solvent, and an acid is added as needed, for example, in the form of a solid, a liquid, a solution or a gas. · The acid portion of the RS-dibasic acid addition salt contained in the residue formed in the step 为) is an acid which selectively dissolves the R- or S-diol free base and/or I plus Forming a salt and leaving an undissolved substance rich in RS_dibasic acid addition salt to form a residue. The acid used in the RS-diol free base can be: • at the starting R- and S-diol a non-racemic alpha salt of a free base and/or an acid addition salt is present in the solvent prior to mixing with the solvent; and/or [s] 20 1331605 • with the solvent and the starting R- and S- binary a non-racemic mixture of an alcohol free base and/or an acid addition salt; and/or a non-racemic mixture of the starting R_ and 8_diol free base and/or acid addition salt and Mixing the solvent with the solvent; and/or • a non-racemic mixture of the starting R- and S-diol free test and/or acid addition salt during and/or prior to mixing with the solvent Among them.

The appropriate acid to be used as the inorganic acid from the non-racemic mixture of the starting R- and S-diol free base and/or acid addition salt to form the residue/precipitate of the RS-dibasic acid addition salt For example, hydrochloric acid, hydrobromic acid, and sulfuric acid, or organic acids such as oxalic acid, p-toluenesulfonic acid, methanesulfonic acid, and acetic acid. Preferred acids are hydrobromic acid, hydrochloric acid, and oxalic acid. When such acids are used, the hydrobromide 'hydrochloride salt of the rs-diol and the oxalate salt are formed, preferably in the form of a crystal. Suitable for use as high as 10 equivalents. According to this: η - f υ.4 旲 ears, 0.4-0.6 Mo' or 〇9-1 1 stems j5\; 1 R 〇〇τγ 丨·1 moule, or U·2.2 mol acid to the south Non-racemic mixture of R- and S-diol free bases and/or acid addition salts

Each mole of S- and R-diol; and / or • 0.3-4.0 moles, such as 〇4 〇6 moles, or 〇Μ"mol, or 1.8-2.2 moles of acid to the remainder Each RS-diol included in the substance/precipitate. Wu Dou

In order to increase the ionic strength of the solution, it is possible to add a salt to the solution before, during or after the RS glycolic acid addition salt in step i). For example, it is known in the art how to adjust the additive effect of the salt. 21 Ϊ 331605, which is used to form a residue/precipitate of RS_dibasic acid addition salt from a non-... spin mixture of starting R- and S-diol free base and/or acid addition salt Suitable solvents for the shoulder are polar and non-polar solvents such as toluene, ethyl acetate, hydrazine, ethyl bromide, THF, alcohols such as isopropanol, acetonitrile, and ketones such as propyl and methyl isobutyl hydrazine, and water. Soil If the residue/precipitate formed in step i) is crystalline, the crystal is separated from the final solution phase, preferably by filtration or tilting. It may be desirable to crystallize the crystals by dissolving them in a solvent, preferably by heating, and then cooling the solution, or by cooling to below ambient temperature. Racemic cedar can be formed from a crystalline racemic glycolic acid addition salt via a ring closure reaction. Racemic cedar can be converted to a pharmaceutically acceptable salt thereof, preferably a HBr salt. "If the residue/precipitate formed in step i) is amorphous, but amorphous or oily, or a mixture thereof, step ii) may be repeated until a crystalline product is obtained. To press, day, ?, the above recrystallize one or more attacks. After reading 0j Μ攸 crystal type elimination. The crystal obtained by racemic siplan can be as needed

22 The diol mirror image isomer contained therein is isolated as described below. When desired, crystallization of the RS-dibasic acid addition salt can be initiated by seeding with a racemic crystalline glycolic acid addition salt. The alkyd addition salt can be converted, as desired, to form RS-binary to other acid addition salts or corresponding free bases according to the invention, in accordance with a preferred embodiment of the invention, obtained in steps i), iia) and iib) The free base of RS-monohydric alcohol or the hydrochloride, hydrobromide, and oxalate salt of Rs_diol is preferably in crystalline form.

; Chang 3 R or S - monool free test and / or the final solution phase of the acid addition salt, its extract, or phase can be applied to the conventional purification before the evaporation of the solvent (for example, using activated carbon, chromatography, etc.) Treatment), and/or may be subjected to one or more steps of the Rs_diol free base or RS_dicarboxylic acid addition salt according to the present invention to improve the diol image The mirror image isomer purity of the product product. The R or S monohydric alcohol free test and/or the acid addition salt may be evaporated by using a procedure such as a solvent, or in the case where the final solution phase is acidic.

The phases are separated from the final solution by alkalization followed by separation of the phases or by extraction of R or 8-diol free base and/or acid addition salt followed by evaporation of the solvent. For the final solution phase of the S 11 or S - monohydric alcohol free radical test and / or acid addition salt, the extract thereof, or the phase may be separated from the 1 or s diol free base and / or acid addition salt Prior to precipitation, conventional purification procedures (e.g., treatment using lingual carbon, chromatography, etc., may be suitably employed to precipitate the R- or S-diol to phosphate or oxalate by methods known to those skilled in the art. The R- or S-diol that has been found to remain in the final solution phase is free to detect the image isomer purity of the 23 l33l6〇5 or acid addition salt (in the desired v, the desired isomer and two The ratio between the sum of the isomers, depending on the particular conditions desired, may be as high as -97-98% or even higher (i.e., better). Therefore, s_ made according to the present invention The diol (or R-diol) free base and/or acid addition salt may contain a small amount of R diol (or s diol) free base and / or acid addition salt. In a specific example These may be less than 3%, or more preferably less than 2%, or most preferably less than 1% (the ratio between the isomer contained in a small amount and the sum of the two isomers). The R- or S-monohydric alcohol free test and/or acid addition salt can be purified as described above and isolated from the solvent or the final solution. In one embodiment, the R-glycol free is obtained. Base or acid addition salt 0 In another embodiment, an S-diol free base or an acid addition salt is obtained. When an R- or S-diol free base is obtained, it is optionally taken. Conversion to its acid addition salt. When an R- or S-dibasic acid addition salt is obtained, it is converted to other acid addition salts or corresponding free bases as needed. Pure R- or S-diol free base and/or acid addition salt is mixed with a non-racemic mixture of R- and S-diol free base and/or acid addition salt to give a racemic glycol Free base and/or acid addition salt. The racemic diol can then be obtained by subjecting the racemic diol free base and/or its acid addition salt to one or more precipitations as described above, followed by recrystallization. Free base and / or acid addition salt. R- or S - citrate free test and / or acid addition salt can be freely tested and / or acid addition from the corresponding Re · si 24 1331605 or s-diol Formed via a ring closure reaction but maintained under configuration. The s- cymidine (or R- cypland) free base and/or acid addition salt can be converted to its acid addition salt as desired, preferably oxalate and Recrystallization as needed. The ring closure reaction of the R- or S-diol free base and/or acid addition salt can be carried out in an inert environment by a restorative intermediate, for example in the presence of toluenesulfonium. , as described in EP-B1-347 066. Then, the ring closure reaction is carried out while maintaining the stereochemistry. After that, it is possible to obtain an image or a s_ siplan which is substantially equal to the image isomer purity of the starting diol. Freely tested and/or acid-added salt. %•Red-doped monol free test and/or acid addition salt can be closed in an acidic environment, as described in US 4,650,884, or as described above. Unstable esters are implemented. Therefore, the racemic siplan is obtained. The thus obtained image-isomerically pure R_ or s- celand free base and/or S underdosed salt may be mixed with a non-racemic mixture of R- and S-Cymidine free and/or acid addition salts. A racemic celand free base and/or an acid addition salt is obtained. The racemic sirranin free test and/or acid addition salt can then be obtained by subjecting the cedar free base or its acid addition salt to - or multiple times & then recrystallization to the same as described above. A particular embodiment of the invention relates to a process for the preparation of a racemic glycol free base and/or an acid addition salt thereof and/or an R_ or 3_diol free base or an acid addition salt thereof, which comprises More than 5% by% of the smectic isomers - the starting R- and the S-glycol free base and / or the acid addition salt of the non-racemic mixture is separated into a S-diol or ruler _ diol part and - package 25 丄川005

• The fraction of the alcohol, 1φ ρ - 古·c - - A , , T R--sterol · S-monosterol ratio, etc. at 1 · 1 or than at the beginning R- and s_ The mixture of glycols is closer to ^:1, wherein i) the RS_diol is precipitated from a solvent as a free base or an acid addition salt thereof; u) the precipitate formed is separated from the mother liquor ua If the precipitate is crystalline, recrystallize it as needed or once a day to form a racemic glycol; ub) If the precipitate is not crystalline, repeat the steps 〇 and Lu (1) as needed until Obtaining a crystalline precipitate and recrystallizing the crystalline precipitate one or more times as needed to form a racemic glycol; in) optionally purifying the mother liquor and isolating the S-di from the mother liquor a diol or R_ binary; iv) converting the resulting diol free base to its acid addition salt as needed or converting the resulting glycolic acid addition salt to other acid addition salts as needed or The alkyd addition salt is converted to the corresponding free base as needed. A particular embodiment of the invention relates to a process for the preparation of racemic glycols or their acid addition salts and/or R- or S-diol free bases or acid addition salts thereof, which will contain More than 50% of the non-racemic mixture of the starting R- and S-diols of one of the mirror image isomers is separated into a portion rich in 5-diol or R-diol and includes Part of the RS_diol, wherein the ratio of R-diol: S-diol is equal to 1:1 or closer to 1:1 than in the mixture of starting R- and s-diol , i) precipitating RS-diol from a solvent to a free base or its acid addition] 26 !3316 〇 5 salt form; (. R and S _ ol of a non-racemic mixture will be R- or The S-di-alcohol is cold-solved in the form of a free base or an acid addition salt thereof in the solvent; Η) separating the precipitate formed from the mother liquid lla) if the precipitate is crystalline Recrystallizing it as needed or forming a racemic glycol; nb) if the precipitate is not crystalline, repeat steps 丨) and u) as needed until a crystalline precipitate is obtained and Crystalline The precipitate is recrystallized one or more times as needed to form a racemic diol; 111) the mother liquor is further purified as needed and the sigma-S-diol or binary is isolated from the mother liquor; iv) The obtained diol free base is converted into its acid addition salt as needed or the obtained glycolic acid addition salt is converted into other acid addition salt as needed or the obtained glycolic acid addition salt is converted into a corresponding one as needed. Free base. [Embodiment] The present invention will be clarified by the following examples, but it is not considered to be limiting. EXAMPLES In the following examples, the optical purity was measured by chiral SCFC (Supercritical Fluid Chromatography) HPLC. Example 1 Purification of s-diol by precipitation of racemic binary yeast to a common method: r _ 27 : a mixture of R and s - monohydric alcohol (such as the following) (1 gram) dissolved in Toluene (60 mA) defined in the formula M, "this (60 ml) A. Add hydrochloric acid aqueous solution (32 ml suspension in the case of adding solid sodium sulphate (sufficient

The concentration of NaC1 in water is approximately 1 M). The 亥 曰 曰 、 、 、 、 、 、 、 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 The residue is dried to obtain a miscellaneous _ diol hydrochloric acid stepping on the crystal... The crystallization of a yeast hydrochloride 夂 1 day. The mother liquor was alkalized using an aqueous ammonia solution and the f-benzene layer was separated. Use the hypothyroid shovel to smash the water layer again, and combine the 甲 Γίί s~ glycol. See the details listed in the table. The recovery rate of the substance is almost ‘·'! With the expected weight distribution between individual samples

----ftp | |__0 U Add solid NaCl to the carcass, enough to make the resulting aqueous phase about 1 M NaCM. The liquid was dehydrated with magnesium sulfate and evaporated under reduced pressure to give a small amount of R-glycol. In the following examples, the optical purity was measured by chiral HPLC. Example 2 Purification of S--7C Fermentation 将 t. 28 by crystallization of the racemic binary white mountain from #u C - X* ear

Claims (1)

13^05 —__ ·. The color of the book (more) is the original, the scope of the patent: 1 · the free R- and S-diol from the initial or its acid addition salt - non-racemic Mixture preparation of racemic cedar diol (,, racemic diol) - free test or its acid addition salt and / or corresponding R - or S - glycol free base or its acid addition salt 'Including the following steps: 1) Precipitating a mixture of R_ and S- cypland diols as a free base or an acid addition salt thereof from the solution of the starting non-racemic mixture (, RS_diol) 'Leaves a final solution phase comprising R- and S_diol free base or an acid addition salt thereof, wherein the precipitated Rs glycol comprises R_diol: the ratio of 3-di-sterol is Equivalent to 1 or closer to 1:1 than the starting non-racemic mixture; or mixing the solution of the starting non-racemic mixture with a solvent to preferentially test R- or S-dittanol or its acid Dissolving the salt into the final solution phase, leaving the rS_diol free test or its acid addition salt (4) residue Π) separating the residue/precipitate from the final solution phase; - if the residue/precipitate Object In the form of a crystal, the residue/precipitate may be recrystallized as needed - or multiple times to form a racemic glycol; or one, if the residue/precipitate is not crystalline, repeat step i as needed And step ii) until a crystalline residue, a precipitate is obtained and the crystalline residue/precipitate is optionally provided as s. 丹 m day- or multiple times to form a racemic binary yeast; W) The final solution phase needs to be subjected to further purification V) from the final solution phase to separate S _ _ 兀 * per or R-glycol free base or acid addition salt; 36 1331605 via) the S-two The alcohol or the R-glycol free base is converted to its acid addition salt as needed; the acid addition salt of the R-diol free base is as needed: or the acid addition salt of the R-diol free test is required Vib) The S-dialdehyde or to be converted into other acid addition salts vie) to convert the S-dialdehyde into a corresponding free test. 2. Preparation of S-Cymidine glycol or cedar glycol free test or its acid addition salt from a non-racemic mixture of starting R- and S-diol free base or its acid addition salt The method comprises the steps of: i) precipitating a mixture of R- and S- cypland diols as a free base or an acid addition salt thereof from the solution of the starting non-racemic mixture ("Rs_ binary Alcohol"), leaving a final solution phase where the precipitated RS_diol contains R-glycol: the ratio of S-diol is equal to 丨:1 or is less than the initial non-racea I The tailings are closer to 1. i; or the solution of the starting non-racemic mixture is mixed with a solvent to preferentially add the R- or s-diol free base or its acid The salt is dissolved into the final solution phase, leaving the remainder of the RS-diol free base or its acid addition salt; the residue/precipitate; the liquid phase is applied and the S-binary is purified in one step. Alcohol or R_diol ii) phase separation from the post-sequence solution iii) If necessary, the final solution is iv) separated from the final solution phase and/or its acid addition salt. 3 · According to the method of applying for a patent, the alcohol prepared is an S monohydric alcohol free base or an acid addition salt thereof. 4. The method of claim 2, wherein the 37 1331605 diol is an R-glycol free base or an acid addition salt thereof. 5. A process for the preparation of a racemic cedar diol (, racemic diol, ) free base or an acid addition salt thereof, comprising the steps of: hydrating from a solution of the starting non-racemic mixture a mixture of R- and S_ cyram diols as a free base or an acid addition salt thereof (, rs_diol), leaving a post-removal solution phase in which the precipitated Rs_diol Contains R-*~ · S - -H- 66 tf- /ε, ϊ ^ λ-λ- for the temple at 1:1 or closer to 1:1 than the starting non-racemic mixture; spleen $ L , 4, mixing the solution of the starting non-racemic mixture of 5 hai with a solvent to preferentially dissolve the 戋s _ __ fly-form alcohol free test or its acid addition salt into the final solution phase, leaving _ _ a residue of free RS-formol or its acid addition salt; π) separating the residue/precipitate from the final solution phase; B) if the residue/precipitate is crystalline, Recrystallization needs to be repeated one or more times to form a racemic glycol; if the residue/precipitate is not crystalline, repeat steps 〇 and U) as needed until a crystalline residue/precipitate is obtained The crystalline residue/precipitate is recrystallized as needed - or multiple times to form a racemic glycol. 6. According to the patent application scope i of ^ ^ ^ ^ shell (method, wherein the starting non-racemic mixture contains more than 50% of s_diol. 7. according to the method of claim 1 of the ' The starting non-racemic mixture contains more than 50% of the R-diol. 8 · According to the method of claim 1 of the patent application, in the RS-diol of the residue/precipitate The ratio of R• binary s--alcohol is in the range of 38 1331605 0.5 : 1.5 to 1:1. 9. According to the application, the R ς - n~ The method 'where the residue/sinking substance of RS-monohydrazide and the solution phase of the solution is in the form of a free base or an acid addition salt thereof." _Dihydric alcohol is independent of each other according to the scope of claim 1 A method in which a W free base or an acid addition salt thereof is deposited from the mouth. A solution of a non-"good mixture is precipitated according to the patent application (IV). The RS-diol is precipitated. The racemic mixture obtained or dissolved in a suitable solvent according to the method of claim U of the patent application and the initiation of the acid The non-solution is added after the initial non-racemic mixture or the initial non-phasing compound is dissolved in a suitable solvent; during the dissolution of the initial non-racemic mixture in the primary coolant and/or before the presence of the solvate In the initial non-racemic mixing during and/or prior to dissolution in the solvent. 13. According to the method of claim 1 of the patent application, the initial non-racemic temperature is 1 Μ - /, the middle system will be 5 hai The 铋# 匕 物 物 铋 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 优先 优先 优先 优先 优先 优先 优先 优先 优先 优先 优先 优先 优先 优先 优先 优先 优先 优先The remainder of the acid addition salt. 14. The method according to the scope of claim i of the patent application, acid addition salt system fly # A a T RS - ^ 'V becomes a residue having an acid moiety containing an acid. According to the method of claim 13, wherein the acid hydrazine is present in the solvent before the initial non-racemic mixture is mixed with the solvent; X' • with the solvent and the starting non-racemic mixture Mix together; and/or • after the initial non-racemic mixture is mixed with the solvent The solvent is mixed; and/or Θ is present in the initial non-racemic mixture during and/or prior to mixing with the solvent. The method of claim 14, wherein the starting non-racemic mixture is Mixing with a solvent selected from the group consisting of toluene, ethyl acetate, diethyl ether, THF, water, alcohols, acetonitrile, ketones, and mixtures thereof. 17) The method according to the scope of the application, wherein the residue / The formation of the precipitate uses an acid selected from the group consisting of HC1, HBr, H2SO4, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, and oxalic acid. 1 8 The method according to claim 17, wherein the acid is selected from the group consisting of HC1, HBr and oxalic acid. The method of claim 1, wherein the residue/precipitate is formed using an acid pair of G2_1q moles; each mole S- and R-di included in the mixture Alcohol. [20] The method of claim i, wherein the residue/^ is formed using 〇.3-4.0 moles of acid per residue/precipitate included per mole of RS_diol. • μ诹 prefers patents The precipitate lost s. The method of claim 1, wherein the residue/precipitate is an RS-glycol free base and the initiation is in accordance with the method of claim 1, wherein the residue/precipitate is RS-diol free base. The non-racemic mixture is a cold towel selected from the group consisting of alkanes, aromatic hydrocarbons, polar solvents, alcohols, and mixtures thereof. 23. The method of claim i, wherein the final solution phase is followed in the step before the S-diol or R•diol free base or its acid addition salt is separated from the final solution. </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; The method of claim 1, wherein the final solution phase is acidic, and by alkalizing the final solution phase, by phase separation or by solvent extraction followed by evaporation of the solvent, from the end The solution phase separates S_ &quot;&quot; alcohol or R-alcohol free test or acid addition salt. 26. According to the method of claim i, wherein R- or S - ^ two /= a sterol free base or an acid addition salt thereof to phase out the S--7L alcohol or a diol-diol free base and/or an acid addition salt from the final solution. 2727. According to the method of the patent scope i Wherein the 5_2 7ti Sj-X&gt; _ _ γ 70 alcohol free base or its acid addition salt is obtained There are a small number of different mirrored Wu constructs. 28. - Preparation of citrin free test or its acid addition salt and (5) s · Xipu: method by: or its acid addition salt * R · Xipu 蔺 free base or its The acid addition salt of ', /, includes the method according to the scope of the patent application, and then the closed loop of 1331605. 29. The method according to claim 6, wherein the initial non-racemic mixture contains more than 70% of a 3-diol. 30. The method of claim 2935, wherein the starting non-racemic mixture contains more than 9% by weight of 8-diol. &gt; 31. According to the scope of application The method of item 7, wherein the starting non-racemic mixture contains more than 7% by weight of a hanol. The method of claim 31, wherein the starting non-racemic mixture contains more than 90% of the R-diol. 33. According to the scope of application for patents / Shen Dian in RS-diols 05 : 1.5 ^ 0.9 : 1.1 &gt; 〇 95 : or 1 · 1 〇 8 of the method, in which the residue diol: The ratio of S-diol is 1.05, 〇·99: 1.01, 0.98: 1.02. 34. According to the method of claim 16, wherein the solvent is k from isopropanol, acetone, methyl isobutyl A mixture of ketones and theirs. Rs•乂. According to the method of claim 18, wherein the hydrobromide, hydrochloride or oxalate of the alcohol is formed. ^According to the formation of the remainder/mouse in the 19th item of the patent application (4), an acid selected from the group consisting of 〇2 〇4 耳, 〇4_〇6, including each of the Mo-S- and R- The diol is scooped by /9-1.1 moles and ^2.2 moles in the starting non-racemic mixture. 7. The method according to the scope of the patent application 帛 2G, wherein the formation of the residue / mole is selected from the following The amount of acid 0.4-0.6 moles, 0 9-u and 1.8-2.2 moles of acid per residue contained in the residue/precipitate was 42 1331605 moles of RS-diol. 38. The method of claim 22, wherein the solvent is selected from the group consisting of heptane, hexane, toluene, benzene, xylene, acetonitrile, methanol, isopropanol, methyl isobutyl ketone, and the like. mixture. 39. The method of claim 26, wherein the R-glycol or S-glycolic acid addition salt is precipitated as a phosphate or oxalate salt. 40. The method according to claim 27, wherein the S-diol or R-diol free base or an acid addition salt thereof obtained contains less than 3% of a mirror image isomer. The method of claim 40, wherein the S-glycol or R-diol free base or an acid addition salt thereof contains less than 2% of a mirror image isomer. 42. The method of claim 41, wherein the S-diol or R-diol free base or acid addition salt thereof is obtained containing less than 1% of a mirror image isomer. Pick up, pattern: no 0 43