Description PROCESS FOR PREPARING 4-CHLORO-3-HYDROXYBUTANOIC ACID ESTER
[i]
Technical Field
[2]
[3] The present invention relates to a process for preparing 4-chbro-3-hydroxybutanoic acid ester. More specific^, the present invention relates to a process for preparing 4-chbro-3-hydroxybutanoic acid ester of high optical and chemicd purity in high yield through the optimization of the reaction pH, addition order of reactants, and/or amounts, etc. of reaction sdvent and the reactants.
[4]
Background Art
[5]
[6] 4-Chk>ro-3-hydroxybutanoic acid ester of the fdbwing formula:
[7]
[8]
[9]
[10] , wherein R is C^alkyl,
[11] is a useful intermediate for preparing atorvastatin, a therapeutic agent of hyper- fipidemia.
[12]
[13] A process for preparing the above 4-chbro-3-hydroxybutanoic acid ester, hiown in the art, comprises the fdbwing steps of:
[14] 1) reacting epichbrohydrin of the fdbwing formula:
[15]
[16]
[17]
[18] with a cyanide of the fdowing formula:
[19] M(CN)
a
[20] (3)
[21]
[22] , wherein M is a cation, and n is an integer of 1 to 3,
[23] to form 4-chbro-3-hy droxy butyronitiie of the fciowing formula:
[24]
[25]
[26]
[27] 2) subjecting the 4-chbro-3-hydroxybutyionitrile of the above formula (4) to acid hydrctysis to form the 4-chbro-3-hydroxybutanoic acid ester of the above formula (1).
[28]
[29] The above process may be depicted by the fciowing reaction scheme:
[30]
[31]
[32]
[33] First, some processes to prepare 4-chbro-3-hydroxybutyronitxie in step 1) are kiown in the art reacting chirai epichbrohydrin with liquid hydrogen Cyanide under heating in a sealed container for severs! days [Hormann, Ber., 1879,12,23], empbying hydrogen cyanide with potassium cyanide as a catatyst [F. Binon, Bull. Soc. Chim. Beiges., 1963, 72,166], performing the reaction under the neutral condition by simultaneously introducing a mixed aqueous sdution of sodium cyanide and potassium cyanide with an aqueous sdution of acetic acid [Culvenor, J. Chem. Soc., 1950,3123], etc.
[34]
[35] However, the Hormann's method empbying Squid hydrogen cyanide is not suitable for commercial production because liquid hydrogen cyanide is very dangerous to hande, and it requires extreme^ bng reaction time and a speciafy designed pressure-resistant container for industrial use. The Binon's method also has the same problem of using hydrogen cyanide. Also, the Culvenor's method has difficulty to contrd the speed of simultaneous introduction of an aqueous metal cyanide sdution
with an acid sdution to maintain the optimd pH.
[37] Ii order to resdve the above-mentioned problems and to provide an economical process suitable for large-scale industrial production, various improved processes have been developed. For example, Japanese Patent No. 5310671 by Daiso Co., Ltd. in Japan disdoses a process characterized by maintaining the reaction pH within the basic range of 8 to 10 by simultaneous^ introducing an inorganic acid sdution and an aqueous sdution of alkzfi metd cyanide into an aqueous sdution of epichbrohydrin. This process tried to resdve such problems as formation of the side products of
3- hydroxyglutaromtrie and 4-hydroxycrotonifcrie under basic pH and elevated temperature, as described in Org. Syntheses, CV 5,614. However, it is not so easy to adjust pH by simultaneously introducing sulfuric acid sdution and basic aqueous cyanide sdution into the epichbrohydrin sdution, and particular^, the heat of neu¬tralization occurred from simultaneous introducing an acid and a base may be a concern in terms of the contrd of the reaction temperature.
[38]
[39] Subsequent^, a process to prepare 4-chbro-3-hydroxybutanoic acid ester in step 2) comprises the steps of subjecting 4~chbro-3-hydroxybutyronitrile to hydrctysis under aqueous acidic conditions to form a carboxyfic acid (4-chbro-3-hydroxybutanoic acid), which was further transformed to
4- chbro-3-hydroxybutanoic acid ester. This process may be depicted by the fdbwing reaction scheme:
[40]
[41]
[42]
[43] h the above reaction, R-C(OH)=NH is formed as an intermediate, and hydrctysis of the imine (=NH) forms a carboxyfic acid. The reaction is a conventional hydrctysis empbying an aqueous acid sdution, and has such problems that it should be performed in the reflux temperature, and often stops in the amide intermediate which can hardfy be hydrcfyzed.
[45] Another kiown process (Rimer's reaction) comprises the steps of dissolving 4-chbro-3-hydroxybutyronitrile in an alcohol or a mixed sdution of an afcohd and an inert sdvent, performing the reaction at a tow temperature for a bng time with Mowing hydrogen chbride gas thereto to form an imidate as an intermediate, and hy- drctyzing the imidate with an aqueous acid sdution. The above process may be depicted by the fciowing reaction scheme:
[46]
[47]
[48]
[49] , wherein R' is C1CH CH(OH)CH -, and R" is C alkyl.
2 2 1-4
[50]
[51 ] According to the process described in a literature by Geza Braun, J. Amer. Chem. Soc., 1930,52,3167, the reactants are coded down in a mixed sdution of ethand and ethjl ether, the reaction is performed with an extreme excess of hydrogen chbride gas over several hours, and the reaction mixture is concentrated and the residual hydrogen chbride gas is removed through distiling the sdvent therefrom. An imidate compound obtained from the above reaction is dissdved in water again, and hydrdyzed to obtain the desired ester compound, h this case, if the excessive hydrogen chbride is not removed, a carbox>ic acid is formed as a byproduct with the eth>l ester, and thus, the concentration should be performed as complete^ as possible when distifing the sdvent under reduced pressure. For industrial application, the above process has several problems such that an anti-rust reactor should be very carefufy selected due to the presence of excessive hydrogen chbride and its productivity is very bw due to an extreme^ bng reaction time, fc addition, the present inventors performed the reaction according to the above literature, and as a result, confirmed that the reaction has such inconveniences that an impurity with unkiown structure is formed, and so the desired product of high purity can be obtained orfy after a purification process such as dis- tilation, and the reaction takes a bng time of several days.
[52]
[53] Therefore, in order to resdve the above problems and to provide an economical process suitable for large scale industrial production, various improved processes have been devebped. For example, Japanese Patent No. 04124157 disdbses a process for preparing 4-chbro-3-hydroxybutanoic acid ester of high optical activity. This process provides 4-chbro-3-hydroxybutanoic acid ester with high opticd activity by heating 4-chbro-3-hydroxybutyronitrie in a concentrated hydrochbric acid sdution, extracting the sdution to obtain 4-chbro-3-hydroxybutanoic acid, and esterifying the is dated caiboxyic acid with a smal amount of an acid catityst in an afcohcfic sdvent According to the patent, 4-hydioxy-3-hydroxybutyronitrie is treated with concentrated hydrochbric acid and heated to obtain an aqueous sdution of 4-chbro-3-hydroxybutanoic acid. The resulting aqueous sdution is concentrated under reduced pressure and extracted with a sdvent. The extract concentrate is purified with a cdumn chromatography, and then, reacted with a suitable aicohd under an acid catafysis to afford 4-chbro-3-hydroxybutanoic acid ester. However, this process is not suitable for practical application, either, in that the empbyment of an extreme^ excessive amount of concentrated hydrochbric acid fdbwed by concentration under reduced pressure may cause corrosion of apparatus. Moreover, the concentration of water empbyed as a reaction sdvent under reduced pressure is not easy and further, several-times of repeated extractions of 4chbro-3-hydroxybutanoic acid are required due to its good sdubity into an aqueous phase.
[54]
Disclosure of the Invention
[55]
[56] The present inventors have performed extensive studies to resdve the above described problems of the prior arts. As a result, the present inventors found a certain optimal range of the reaction pH. The inventors also found that the desired product with high opticd activity can be obtained in high purity and yield by switching the order of addition of reactants, and/or modifying lands, amounts, etc. of a reaction sdvent and the reactants.
[57]
[58] Therefore, the purpose of the present invention is to provide a process that can prepare 4-chbro-3-hydroxybutanoic acid ester of high optical activity and purity in good yield, bw cost, and high suitability for large scale operation.
[59]
[60] One aspect of the present invention provides a process for preparing 4chbro-3-hydroxybutyronitrile of formula:
[62]
[63]
[64] , comprising the step of
[65] 1) reacting epichbrohydrin of formula:
[66]
[67]
[68]
[69] with a cyanide of formula:
[70] M(CN)
[71] (3)
[72]
[73] , wherein M is a cation, and n is an integer of 1 to 3,
[74] under the pH condition ranging from 7 to 8, particularly from 7.3 to 7.8, to form the 4-chbro-3-hydroxybutyronitrie of formula (4).
[75]
[76] A second aspect of the present invention provides a process for preparing 4-chbro-3-hydroxybutanoic acid ester of formula:
[77]
[78]
[79]
[80] , wherein R is C dk)l,
[81] comprising the step of
[82] 2a) dissdving 4-chbro-3-hydroxybutyronitrfle of formula (4) in an alcohdic sdvent, and then, reacting it with hydrogen chbride, or
[83] 2b) reacting the 4-chbro-3-hydroxybutyronitrile of formula (4) in an alcohdic sdvent saturated with hydrogen chbride,
[84] to form the 4-chbro-3-hydroxybutanoic acid ester of formula (1).
[85]
[86] A third aspect of the present invention provides a process for preparing
4-chbro-3-hydroxybutanoic acid ester of formula (1) comprising the above step 1) and step 2a) or 2b).
[88] Hereinafter, the present invention wit be explained in detai.
[89]
[90] 1) Step 1): Preparation of 4-chIoro-3-hydroxybutyronitrile
[91]
[92] The present inventors found that the composition of the reaction product varies depending on the pH at which epichbrohydrin reacts with cyanide, as depicted in the fdowing reaction scheme:
[93]
[94] (4)
[95]
[96] First, when the reaction sdution is acidic, the ring-opening reaction of epichbrohydrin is accelerated by acid catatysis, to form considerable amounts of
3,4-dihydroxybutyronitrie and 1,3-dichbroisopropand, and their amounts increase as the acidity becomes stronger.
[97]
[98] Second, when the reaction sdution is basic, the epoxy ring is attacked by cyanide, and thus, the desired 4-cyano-3-hydroxybutyronitrie is produced as a main product, but hydroxyl anion formed during the reaction attacks the chbrometh)! group in- tramdecularfy to form another epoxy ring resulting in 3,4-epoxybutyronitrie, which is attacked again by cyanide group to form 3-hydroxy$utaronitrile. Alternatively, |3- eHmination reaction of 3,4-epoxybutyronitrie by the action of base forms 4-hydroxycrotononitrie.
[99]
[100] Therefore, as discovered by Daiso Co., Ltd., the present inventors confirmed that it
is very important to adjust the pH of the reaction sdution. However, whie Daiso Co., Ltd, reported that the pH in the range of 8 to 10 is the most preferable, the present inventors newly found that the formation of byproducts can be minimized and the reaction can be performed most efficient^ by adjusting the pH of the reaction sdution to the range of 7 to 8, particular^ 7.3 to 7.8. Moreover, since it is not easy to simul- taneousfy introduce the two reactants, one of which is acidic and the other is basic, with delicately maintaining the reaction pH within a certain range, the present inventors devebped a process that can very strictly contrd the conditions of the reaction, by switching the order of addition of the reactants in step 1).
[101]
[102] Specificafy, in the present invention, metal cyanide and an inorganic acid are introduced into a reactor and the pH is adjusted to the desired range. Subsequently, epichbrohydrin is added thereto to carry out the reaction under the condition in which the pH is contrcled in a relative^ simple manner. That is, the pH of the reaction sdution is adjusted to 7.0 to 8.0, preferabfy 7.3 to 7.8, and then, epichbrohydrin is added thereto diopwise.
[103]
[104] The knds of metal cyanide used for the above process indude an alkafi metal cyanide such as sodium cyanide, potassium cyanide, etc., calcium cyanide, barium cyanide and the like, but sodium cyanide and potassium cyanide are particular^ preferable because they are readfy available and have been widefy used in the industry. The knds of inorganic acid introduced for adjusting the pH indude hy¬drochbric acid, nitric acid, sufuric acid, sulfonic acid, phosphoric acid, methanesulfonic acid, etc. Preferable are suFonic acid, sulfuric acid and hydrochbric acid.
[105]
[106] The reaction with the inorganic acid may be preformed in a mixture of aicohd and water, or water, and preferabfy, in water, and water may be used in the weight ratio of 2 to 20 based on the weight of epichbrohydrin. However, considering stirring efficiency and economical aspect, it is preferable to use water in the weight ratio of 3 to 6, more preferabfy 3 to 4. The reaction temperature may be in the range of 0 to 90 °C, but the temperature range of 10 to 40 °C is preferable to maintain reasonable reaction rate, and to suppress the formation of byproducts. Particularly, the temperature range of 15 to 25 °C is the most preferable.
[108] Upon completion of the reaction, salt compound formed therefrom may be filtered depending on the lands of metal cyanide and acid introduced into the reaction sdution, and the filtrate is extracted with an organic sdvent, and the extract is concentrated to obtain the desired 4-chbro-3-hydroxybutyronitrie. The suitable lands of extraction sdvent indude tduene, butand, ethyl acetate, butyl acetate, dichbromethane, etc. b terms of extracting capacity, ethyl acetate, butyl acetate, butand, dichbromethane, etc. are preferable, and ethyl acetate and dichbromethane are more preferable.
[109]
[110] 2) Step 2): Preparation of 4-chLoro-3-hydroxybutanoic acid ester
[HI]
[112] h this step, the present inventors tried to empby minimal amount of acid and to omit a step of extracting 4-chbro-3-hydroxybutanoic acid as an intermediate, and si¬multaneously, to obtain the desired product in high purity and yield for a shortened period of time. As a result, the present inventors found that the desired carboxyfic acid ester can be rapidy prepared in high purity by dissdving
4-chbro-3-hydroxybutyronitrile in an dcohcfic sdvent and bubbling hydrogen chbride gas thereto. Also, the same reaction profiles could be obtained by using an alcoholic sdvent preliminary saturated with hydrogen chbride gas.
[113]
[114] The alcoholic sdvent used in this step may be C ^dcohd. 1 may be used atone, or used in combination with another sdvent. h that case, diethyl ether or diisopropyl ether is preferable as co-sdvent. Most preferabfy, the aifcohofic sdvent is used atone. The weight-by-weight ratio of the aicohd to 4-chbro-3-hydroxybutyronitrile may be in the range of 1 to 10, preferably 1.5 to 4, more preferabfy 1.5 to 2.5, in terms of economic^ efficiency and reaction rate.
[115]
[116] The amount of hydrogen chbride may be in the range of 1 to 10 mde equivalents, preferabfy 1 to 6 mde equivalents, for a fast reaction and work-up of the residual hydrogen chbride. The reaction temperature may be in the range of 0 to 80 °C, preferably 15 to 50 °C, more preferabty 15 to 25 °C, considering the purity of reaction, h case that opticafy active epichbrohydrin is used as the starting material, 4-chbro-3-hydroxybutanoic acid ester obtained from the above reaction retains the optical purity.
[117]
[118] h addition, upon completion of the reaction, the present invention has the
advantage to increase the productivity by reducing the steps of reaction through using relative^ very smai amount of alcohdic sdvent which enables direct extraction with an organic sdvent without concentration of alcohdic sdvent, while excess alcoholic sdvent was distfled under reduced pressure in the prior art.
[119]
Best Mode for Carrying Out the Invention
[120]
[121] The present invention wit be more specificity lustrated by the fciowing examples. However, the fciowing examples should not be construed as limiting the scope of the present invention in any way.
[122]
[123] Example 1: Preparation of 4-chloro-3-hydroxybutyronitrile (NaCN/H
so;
[124]
[125] Sodium cyanide (9.93 g) was dissdved in 60 ml of distfled water, and the sdution was coded down in ice bath. To this sdution was added dropwise sulfuric acid of 9.87 g while maintaining the temperature to 20 °C or bwer, and the pH was measured and confirmed to be 7.7. To the above sdution was added 15 g of epichbrohydrin, and then, the mixture was stirred at room temperature. Upon completing the reaction, the reaction sdution was extracted three times with eth>l acetate, and concentrated under reduced pressure to obtain 17.2 g (yield: 89%) of the title compound as deep yelow oil. Chemical purity (GC): 96.5%
[126]
[127] ' H-NMR (CDC1) 5 4.21 (1H, m), 3.66 (2H, d, J=5.6 Hz), 3.03 (1H, d, J=5.6 Hz, - OH), 2.73 (2H, m)
[128]
[129] 13 C-NMR (CDC1) 5 117.1,67.3,47.3,23.3
[130]
[131] Example 2: Preparation of 4-cMoro-3-hydroxybutyronitrile (KCN/H ^ S04)
[132]
[133] The title compound of 17.8 g (yield: 92%) was obtained according to substantia^ the same method as in Example 1 except using potassium cyanide instead of sodium cyanide. Chemical purity (GC): 96.7%
Example 3: Preparation of 4-cbtoro-3-hydroxybutyronitrile (KCN/HCI)

The title compound of 17.4 g (yield: 90%) was obtained according to substantia^ the same method as in Example 1 except using potassium cyanide instead of sodium cyanide and concentrated hydrochbric acid instead of sulfuric acid. Chemical purity (GC): 95.8%

Example 4: Preparation of 4-chloro-3(S)-hydroxybutyronitrile (KCN/H SO )
2 4

The title compound of 17.6 g (yield: 91%) was obtained according to substantia^ the same method as in Example 1 except using potassium cyanide instead of sodium cyanide and (S)-epichbrohydrin as epichbrohydrin. Chemical purity (GC): 96.5%; Optical purity (HPLC): 99.2%ee
. [142]
[143] Example 5: Preparation of 4-chloro-3-hydroxybutanoic acid ethyl ester
[144]
[145] Ethand was coded down, and anhydrous hydrogen chbride gas was bubbled sbwly thereto. The obtained sdution was titrated to prepare 10 N ethand sdution of hydrogen chbride. The ethand sdution of hydrogen chbride of 30 ml was mixed with 11.96 g of 4-chbro-3-hydroxybutyronitrile, and the reaction was performed while heating to 60 °C under nitrogen atmosphere. Upon completing the reaction, the reaction sdution was coded down, and extracted with 30 ml of distied water and 50 ml of ethyl acetate, and the aqueous phase was further extracted twice with 50 ml of eth>l acetate. The extract was cdected and concentrated under reduced pressure to obtain the title compound of 15.5 g (yield: 93%). Chemical purity (GC): 96.8%
[146]
[147] 1H-NMR (CDCn ) 5 4.20-4.30 (1H, m), 4.18 (2H, q, J = 7.3 Hz), 3.55-3.65 (2H, m), 3.17 (1H, br), 2.55-2.70 (2H, m), 1.28 (3H, t, J = 7.3 Hz)
[148]
[149] 13 C-NMR (CDC1) 8 171.8,68.0,61.0,48.2,38.5,14.1
[150]
[151] Example 6: Preparation of 4-cHoro-3-hydroxybu tanoic acid methyl ester
[153] The title compound of 15.8 g (yield: 95%) was obtained according to substantia^ the same method as in Example 1 except using 4-chbro-3(S)-hydroxybutyronitrie as 4chbro-3-hydroxybutyronitrile and methand instead of ethand. Chemical purity (GC): 97.1%; Optical purity (IPLC):99.2%ee
[154]
[155] 1H-NMR(CDQ)64.28 (1H,m),3.70(3H,s),3.61 (2H,m),3.40(1H,br),2.65 (2H,m)
[156]
[157] 13 C-NMR (CDCU 6 172.2,68.0,52.0,38.2,38.8
[158]
Industrial Applicability
[159]
[160] According to the present invention, 4-chbro-3-hydroxybutyronitrie of high purity can be obtained in high yield by reacting epichbrohydrin with cyanide at the pH range of 7 to 8, particular^, 7.3 to 7.8, preferabty by adjusting the pH to the above range by preliminarily mixing aqueous metal cyanide with an inorganic acid at room temperature and room pressure, and then, adding epichbrohydrin thereto to perform the reaction. Also, 4-chbro-3-hydroxybutyronitrile with high optical activity can be obtained with using chiral epichbrohydrin. Moreover, 4-chbro-3-hydroxybutanoic acid ester can be prepared on a large scale in high purity and yield through one-step reaction from 4chbro-3-hydioxybutyronitrile. Further, from 4chbro-3-hydroxybutyronitrie with optical activity, 4-chbro-3-hydroxybutanoic acid ester retaining the optical activity can be obtained in high yield and purity.

Claims
[ 1 ] 1. A process for preparing 4-chbro-3-hydroxybutyronitrile of formula:
[2]
, comprising the step of
1) reacting epichbrohydiin of formula:
[3]
with a cyanide of formula: M(CN)
n
(3)
, wherein M is a cation, and n is an integer of 1 to 3, under the condition of pH ranging from 7 to 8, to form the 4-chbro-3-hydroxybutyronitrile of formula (4).
[4] 2. A process for preparing 4-chloro-3-hydroxybutanoic acid ester of formula:
[5]
, wherein R is C atkvi, u
comprising the step of
2a) dissolving 4-chbro-3-hydroxybutyronitrfle of formula:
[6]
in an sicohcfic solvent, and then, reacting it with hydrogen chloride, or 2b) reacting the 4-chbro-3-hydroxybutyronitrile of formula (4) in an aJcohofic sdvent saturated with hydrogen chloride, to form the 4-chbro-3-hydroxybutanoic acid ester of formula (1).
[7] 3. A process for preparing 4-chbro-3-hydroxybutanoic acid ester of formula:
[8]
, wherein R is as defined in Claim 2, comprising the steps of:
1) reacting epichtorohydrin of formula:
[10] with a cyanide of formula: M(CN)
n
(3)
, wherein M and n are each as defined in Claim 1, under the condition of pH ranging from 7 to 8, to form 4chbro-3-hydroxybutyronitrile of formula:
[11]
(4) ;and
2a) dissolving 4-chbro-3-hydroxybutyronitrile of formula (4) in an afcohdic solvent, and then, reacting it with hydrogen chloride, or 2b) reacting 4-chbro-3-hydroxybutyronitrie of formula (4) in an aJcohcfic solvent saturated with hydrogen chloride, to form the 4-chbro-3-hydroxybutanoic acid ester of formula (1).
[12] 4. The process of Claim 1 or 3, wherein the pH is adjusted in the range of 7.3 to 7.8.
[13] 5. The process of Claim 1 or 3, wherein the pH is adjusted by adding an inorganic acid to the cyanide sdution, and then, epichbrohydrin is added thereto.
[14] 6. The process of Claim 5, wherein the inorganic acid is selected from the group consisting of hydrochbric acid, nitric acid, sufuric acid, sulfonic acid, and phosphoric acid.
[15] 7. The process of Claim 6, wherein the inorganic acid is sulfuric acid or con¬centrated hydrochbric acid.
[16] 8. The process of Claim 1 or 3, wherein the cyanide is sodium cyanide or potassium cyanide.
[17] 9. The process of Claim 2 or 3, wherein the alcohcfic sdvent is methanol or ethand.
[18] 10. The process of Claim 2 or 3, wherein the hydrogen chloride is anhydrous hydrogen chbride gas.
[19] 11. The process of Claim 2 or 3, wherein the weight-by-weight ratio of the alcohdic sdvent to 4-chbro-3-hydroxybutyronitrile is in the range of 1.5:1 to 2.5:1.
[20] 12. The process of any one of Claims 1 to 3, wherein epichbrohydrin or 4-hydroxybytyronitrle has optical activity.